Substituted azole acid derivatives useful as antidiabetic and antiobesity agents and method

ABSTRACT

Compounds are provided which have the structure  
                 
 
wherein Q is C or N; R 2a , R 2b , R 2c , X 1  to X 7 , R 1 , R 2 , R 3 , R 3a , R 4 , A, Y, m, and n are as defined herein, which compounds are useful as antidiabetic, hypolipidemic, and antiobesity agents. The present invention further provides a method for treating obesity and dyslipidemia in mammals including humans through simultaneous inhibition of peroxisome proliferator activated receptor-γ (PPARγ) and stimulation of peroxisome proliferator activated receptor-α (PPARα).

This application is a Divisional of U.S. patent application Ser. No.10/294,525 filed Nov. 14, 2002, which is a continuation-in-part of U.S.patent application Ser. No. 10/153,454 filed May 22, 2002, nowabandoned, which claims priority from U.S. provisional application No.60/294,380 filed May 30, 2001 which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel substituted azole acidderivatives which modulate blood glucose levels, triglyceride levels,insulin levels and non-esterified fatty-acid (NEFA) levels, and thus areparticularly useful in the treatment of diabetes and obesity, and to amethod for treating diabetes, especially Type 2 diabetes, as well ashyperglycemia, hyperinsulinemia, hyperlipidemia, obesity,atherosclerosis and related diseases employing such substituted acidderivatives alone or in combination with another antidiabetic agentand/or a hypolipidemic agent and/or other therapeutic agents. Thepresent invention also relates to a method for treating obesity anddyslipidemia in mammals including humans through simultaneous inhibitionof peroxisome proliferator activated receptor-γ (PPARγ) and stimulationof peroxisome proliferator activated receptor-α (PPARα). The inventionfurther provides a list of target genes wherein their expression isaltered in adipose (fat) tissue through PPARγ antagonist activity toachieve anti-obesity, insulin sensitivity and cardiovascular diseasebenefits.

BACKGROUND OF THE INVENTION

In mammals, including humans, adipocytes (fat cells) store excess energyin the form of triglycerides at times of nutritional excess (see Lowell,Cell, 99: 239-242, 1999). During starvation, stored triglycerides aredegraded to fatty acids in adipocytes in order to supplement nutritionaland energy requirements. Conditions in which excess adipose tissueaccumulation, achieved either through recruitment of progenitor cells(pre-adipocytes) to become adipocytes (differentiation) and/or throughexpansion of the pre-existing adipocytes (hyperplasia and hypertrophy),leads to obesity and insulin resistance (see Lowell, Cell, 99: 239-242,1999). Because, hypertrophied adipocytes (which are consideredrelatively less metabolically active) produce excessive amounts of fattyacids and cytokines which in turn act to reduce insulin signaling andglucose uptake in skeletal muscle and adipocytes, two major glucoseutilizing tissues (see Hotamisligil, et al., Science, 259: 87-90, 1993;Lowell, Cell, 99: 239-242, 1999). Obese individuals frequently sufferfrom inadequate energy expenditure, high fat content in skeletal muscle,liver and plasma, insulin resistance, hypertension, atherosclerosis andcardiovascular diseases (see Rosenbaum et al., New. Eng. J. Med. 337:396-407, 1997, see Friedman, Nature, 404: 632-634, 2000). Conditionssuch as seen in lipodystrophic syndrome patients with severely depletedfat depot leads to reduced body weight, increased lipid content inplasma, liver and skeletal muscle which in turn pre-dispose the patientsto insulin resistance and Type 2 diabetes (see Arioglu et. al., Annalsof Int. Med, 2000,133:263-274). The primary cause of these abnormalitiesappears to be due to relatively small amounts of adipose tissueavailable for safe storage of lipids.

Obesity is a common clinical problem in most developed nations and isalso rapidly becoming a major health concern in developing nations.Overweight individuals frequently suffer from several metabolicdisorders such as dyslipidemia, insulin resistance and Type 2 diabetes.These individuals also frequently suffer from hypertension,atherosclerosis and increased risk for cardiovascular diseases (seeFriedman, Nature, 404: 632-634, 2000).

Peroxisome Proliferator Activated Receptors (PPARs) are members of thenuclear hormone receptor family of ligand regulated transcriptionfactors (see Willson, et al., J. Med. Chem., 43: 527-550, 2000, Kerstenet al., Nature, 405: 421424, 2000). Three PPAR isoforms, PPARγ, PPARα,and PPARδ have been isolated from various mammalian species includinghumans. These receptors, as a class, form obligate heterodimers withtheir binding partner RXRα, and are activated by diet derived long chainfatty acids, fatty acid metabolites and by synthetic agents (seeWillson, et al., J. Med. Chem., 43: 527-550, 2000). It is now welldocumented that PPARs, through regulation of genes in glucose and lipidmetabolism pathways, play a major role in maintaining glucose and lipidhomeostasis in mammals including human.

PPARγ is a principal regulator of pre-adipocyte recruitment anddifferentiation into mature adipocytes and lipid accumulation in matureadipocytes (see Tontonoz et al., Current Biology, 571-576, 1995).Activators of PPARγ promote pre-adipocyte differentiation, lipid storagein mature adipocytes and act as insulin sensitizing anti-diabetic agents(see Tontonoz et al., Current Biology, 571-576, 1995; Lehmann et al., J.Biol. Chem., 270: 12953-12956, 1995; Nolan et al. New. Eng. J. Med.,331: 1188-1193; Inzucchi et al., New Eng. J. Med., 338: 867-872, 1998,Willson, et al., J. Med. Chem.: 43: 527-550, 2000, Kersten et al.,Nature, 405: 421424, 2000). The PPARγ induced anti-diabetic activity ishowever, frequently accompanied by some body weight gain in animalmodels and in humans. PPARγ expression is significantly elevated in theadipose tissue of obese individuals (see Vidal-Puig et al., J. ClinicalInvestigation, 99: 2416-2422, 1997), and a mutation which generatedconstitutively active PPARγ is associated with severe obesity (seeRistow et al., New England J. Med., 339:953-959, 1998). Partial loss ofPPARγ expression leads to resistance to diet induced obesity inheterozygous PPARγ knock-out mice (see Kubota et al. Mol. Cell;4:597-609, 1999) and lower body mass index in human with a proline toalanine change at amino acid position 12 (see Deeb et al NatureGenetics, 20:284-287, 1998). Relatively more severe loss of human PPARγactivity through dominant negative mutations, which abolish ligandbinding to the receptor, leads to hyperlipidemia, fatty and liverinsulin resistance, (see Barroso et al. Nature, 402, 860-861, 1999). Themajor cause of the abnormalities appears to be due to relatively smallamounts of adipose tissue available for safe storage of lipids. Thesemouse and human findings show therefore, a role for PPARγ in theinduction and or progression of obesity and suggest that inhibition ofPPARγ will lead to a reduction in adiposity and obesity. These findingsalso suggest that such a reduction is likely to lead to higher plasmafree fatty acids and hyperlipidemia and development fatty liver andinsulin resistance

The PPARα isoform regulates genes in the fatty acid synthesis, fattyacid oxidation and lipid metabolism pathways (see Isseman and Green,Nature, 347: 645-649, 1990; Torra et al., Current Opinion in Lipidology,10: 151-159, 1999; Kersten et al., Nature, 405: 421424, 2000). PPARαagonist (such as fenofibrate, gemfibrozil) treatment enhance fatty acidoxidation in the liver and muscle, reduce fatty acid and triglyceridesynthesis in the liver and reduce plasma triglyceride levels (seeKersten et al., Nature, 405: 421424, 2000). In patients with hightriglycerides and low HDL-cholesterol treatment with PPARα agonists leadto an increase in plasma HDL-cholesterol, decrease in plasmatriglycerides and reduction in both primary and secondary cardiac events(see Balfour et al., Drugs. 40: 260-290, 1990; Rubins et al., New Eng.J. Med., 341: 410-418, 1999).

Therefore, by combining PPARγ antagonist activity and PPARα agonistactivity in a single dual acting compound or in a formulation, it ispossible to inhibit PPARγ and treat obesity without causinghyperlipidemia, fatty liver and insulin resistance. The presentinvention shows a novel method of treatment of obesity by combining twodifferent activities, the PPARγ antagonist activity and PPARα agonistactivity, to reduce adiposity and body weight without causinghyperlipidemia and insulin resistance. The invention proposes that theobese, hyperlipidemic and insulin resistant Type 2 diabetic patients canbe treated with a dual PPARγ antagonist/PPARα agonist or a PPARγantagonist and a PPARα agonist in combination with a lipid loweringagent and an anti-diabetic agent. The invention also provides a list oftarget genes wherein their expression is altered in adipose (fat) tissuethrough PPARγ antagonist activity to achieve anti-obesity, insulinsensitivity and cardiovascular disease benefits.

In accordance with the present invention, substituted acid derivativesare provided which have the structure I

wherein m is 0, 1 or 2; n is 0, 1 or 2;

Q is C or N

A is (CH₂)_(x) where x is 1 to 5; or A is (CH₂)_(x) ¹, where x¹ is 2 to5, with an alkenyl bond or an alkynyl bond embedded anywhere in thechain; or A is —(CH₂)_(x) ²—O—(CH₂)_(x) ³— where x² is 0 to 5 and x³ is0 to 5, provided that at least one of x² and x³ is other than 0,

X₁ is CH or N

X₂ is C, N, O or S;

X₃ is C, N, O or S;

X₄ is C, N, O or S, provided that at least one of X₂, X₃ and X₄ is N;

X₅ is C, N, O or S;

X₆ is C or N;

X₇ is C, N, O or S, provided that at least one of X₅, X₆ or X₇ is N.

In each of X¹ through X₇, as defined above, C may include CH.

R¹ is H or alkyl;

R² is H, alkyl, alkoxy, halogen, amino or substituted amino;

R^(2a), R^(2b) and R^(2c) may be the same or different and are selectedfrom H, alkyl, alkoxy, halogen, amino or substituted amino;

R³ and R^(3a) are the same or different and are independently selectedfrom H, alkyl, arylalkyl, aryloxycarbonyl, alkyloxycarbonyl,alkynyloxycarbonyl, alkenyloxycarbonyl, arylcarbonyl, alkylcarbonyl,aryl, heteroaryl, cycloheteroalkyl, heteroarylcarbonyl,heteroaryl-heteroarylalkyl, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino,heteroaryloxycarbonylamino, heteroaryl-heteroarylcarbonyl,alkylsulfonyl, alkenylsulfonyl, heteroaryloxycarbonyl,cycloheteroalkyloxycarbonyl, heteroarylalkyl, aminocarbonyl, substitutedaminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl,cycloheteroalkyl-heteroarylalkyl; hydroxyalkyl, alkoxy,alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl,arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl,haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl,aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl, arylthioarylcarbonyl,alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl,heteroaryloxyarylalkyl, aryloxyarylcarbonyl,aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl,aryloxyalkyloxycarbonyl, arylalkylsulfonyl, arylthiocarbonyl,arylalkenylsulfonyl, heteroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl,heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl,aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl,arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl,alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl,heteroarylarylalkyl, arylcarbonylheteroarylalkyl,heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl,aminocarbonylarylarylalkyl;

Y is CO₂R⁴ (where R⁴ is H or alkyl, or a prodrug ester) or Y is aC-linked 1-tetrazole, a phosphinic acid of the structureP(O)(OR^(4a))R⁵, (where R^(4a) is H or a prodrug ester, R⁵ is alkyl oraryl) or a phosphonic acid of the structure P(O)(OR^(4a))₂;

(CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³, (CH₂)_(m), and(CH₂)_(n) may be optionally substituted with 1, 2 or 3 substituents;

including all stereoisomers thereof, prodrug esters thereof, andpharmaceutically acceptable salts thereof.

Preferred are compounds of formula I of the invention having thestructure IAIA

More preferred are compounds of formula I of the invention having thestructures IBIB

In the above compounds, it is most preferred that R^(2a), R^(2b) andR^(2c) are each H; R¹ is alkyl, preferably CH₃; x² is 1 to 3 and x³ is0; R² is H; m is 0 or (CH₂)_(m) is CH₂ or CHOH or CH-alkyl, X₂, X₃, andX₄ represent a total of 1, 2 or 3 nitrogens; (CH₂)_(n) is a bond or CH₂;R³ is aryl, arylalkyl or heteroaryl such as thiophene or thiazole, mostpreferably phenyl or phenyl substituted with alkyl, polyhaloalkyl, halo,alkoxy, preferably CF₃ and CH₃, R^(3a) is preferably H or alkyl.

Preferred compounds of the invention include the following:

The present invention describes the discovery of dual PPARγantagonist/PPARα agonist activity in a single molecule. The inventionshows that administration of a dual PPARγ antagonist/PPARα agonist toseverely diabetic, hyperlipidemic and obese db/db mice leads to areduction in plasma triglycerides and free fatty acid levels, without achange in glucose levels. The present invention shows thatadministration of a dual PPARγ antagonist/PPARα agonist to adiet-induced obese mice leads to reduced body fat content and reducedfat in liver without inducing hyperlipidemia and or insulin resistance.The invention provides a list of target genes wherein their expressionis altered in adipose (fat) tissue through PPARγ antagonist activity toachieve anti-obesity, insulin sensitivity and cardiovascular diseasebenefits.

Accordingly, one object of the present invention is to provide a novelmethod for treating obesity in a mammal, including human, comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a single compound or combination of compounds thatsimultaneously inhibits PPARγ and activates PPARα.

Another object of the present invention provides a method for treatingmetabolic syndrome (obesity, insulin resistance and dyslipidemia) in amammal, including a human, comprising administering to the mammal inneed of such treatment, a therapeutically effective amount of anycombination of two or more of the following compounds: a compound orcombination of compounds that antagonize PPARγ, activates PPARαactivity, an anti-diabetic compound such as but not limited to insulin,metformin, insulin sensitizers, sulfonylureas, aP2 inhibitor, SGLT-2inhibitor, a lipid-lowering agent such as but not limited to statins,fibrates, niacin ACAT inhibitors, LCAT activators, bile acidsequestering agents and a weight reduction agent such as but not limitedto orlistat, sibutramine, aP2 inhibitor, adiponectin.

Another object of the present invention is to provide a list of targetgenes (such as HMGic, glycerol-3-PO₄-dehydrogenase, G-protein coupledreceptor 26, fatty acid transport protein, adipophilin and keratinocytefatty acid binding protein) whose expression can be altered to obtainanti-obesity effects through administration of a PPARγ antagonist anddual PPARγ antagonist/PPARα agonist or through other methods.

Another object of the present invention is to provide a list of targetgenes (such as PAI-1, Renin, angiotensinogen precursor) whose expressioncan be altered to obtain beneficial effects against cardiovasculardiseases through administration of a PPARγ antagonist and dual PPARγantagonist/PPARα agonist or through other methods.

Another object of the present invention provides a pharmaceuticalcomposition for the treatment of obesity comprising: a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundor combination of compounds that simultaneously inhibits PPARγ andactivates PPARα.

Another object of the present invention provides a pharmaceuticalcomposition for the treatment of obesity, insulin resistance and/ordyslipidemia, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound or combination ofcompounds that simultaneously inhibits PPARγ and activates PPARα and ananti-diabetic compound, a lipid-lowering agent and a weight reductionagent.

In addition, in accordance with the present invention, a method isprovided for treating diabetes, especially Type 2 diabetes, and relateddiseases such as insulin resistance, hyperglycemia, hyperinsulinemia,elevated blood levels of fatty acids or glycerol, hyperlipidemia,obesity, hypertriglyceridemia, inflammation, Syndrome X, diabeticcomplications, dysmetabolic syndrome, atherosclerosis, and relateddiseases wherein a therapeutically effective amount of a compound ofstructure I is administered to a patient in need of treatment.

In addition, in accordance with the present invention, a method isprovided for treating early malignant lesions (such as ductal carcinomain situ of the breast and lobular carcinoma in situ of the breast),premalignant lesions (such as fibroadenoma of the breast and prostaticintraepithelial neoplasia (PIN), liposarcomas and various otherepithelial tumors (including breast, prostate, colon, ovarian, gastricand lung), irritable bowel syndrome, Crohn's disease, gastric ulceritis,and osteoporosis and proliferative diseases such as psoriasis, wherein atherapeutically effective amount of a compound of structure I isadministered to a patient in need of treatment.

In addition, in accordance with the present invention, a method isprovided for treating diabetes and related diseases as defined above andhereinafter, wherein a therapeutically effective amount of a combinationof a compound of structure I and another type antidiabetic agent and/ora hypolipidemic agent, and/or lipid modulating agent and/or other typeof therapeutic agent, is administered to a human patient in need oftreatment.

In the above method of the invention, the compound of structure I willbe employed in a weight ratio to the antidiabetic agent (depending uponits mode of operation) within the range from about 0.01:1 to about100:1, preferably from about 0.5:1 to about 10:1.

The conditions, diseases, and maladies collectively referenced to as“Syndrome X” or Dysmetabolic Syndrome (as detailed in Johanson, J. Clin.Endocrinol. Metab., 1997, 82, 727-734, and other publications) includehyperglycemia and/or prediabetic insulin resistance syndrome, and ischaracterized by an initial insulin resistant state generatinghyperinsulinemia, dyslipidemia, and impaired glucose tolerance, whichcan progress to Type II diabetes, characterized by hyperglycemia, whichcan progress to diabetic complications.

The term “diabetes and related diseases” refers to Type II diabetes,Type I diabetes, impaired glucose tolerance, obesity, hyperglycemia,Syndrome X, dysmetabolic syndrome, diabetic complications andhyperinsulinemia.

The conditions, diseases and maladies collectively referred to as“diabetic complications” include retinopathy, neuropathy andnephropathy, and other known complications of diabetes.

The term “other type(s) of therapeutic agents” as employed herein refersto one or more antidiabetic agents (other than compounds of formula I),one or more anti-obesity agents, and/or one or more lipid-loweringagents, one or more lipid modulating agents (includinganti-atherosclerosis agents), and/or one or more antiplatelet agents,one or more agents for treating hypertension, one or more anti-cancerdrugs, one or more agents for treating arthritis, one or moreanti-osteoporosis agents, one or more anti-obesity agents, one or moreagents for treating immunomodulatory diseases, and/or one or more agentsfor treating anorexia nervosa.

The term “lipid-modulating” agent as employed herein refers to agentswhich lower LDL and/or raise HDL and/or lower triglycerides and/or lowertotal cholesterol and/or other known mechanisms for therapeuticallytreating lipid disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A: Illustrates the ability of Compound Y to competitively inhibitthe binding of a labeled authentic PPARγ ligand (BMS-compound A) tohuman PPARγ ligand binding domain.

FIG. 1B: Illustrates the binding of a labeled authentic PPARα ligand(BMS-compound B) to human PPARα binding domain.

FIG. 2: Illustrates the ability of Compound Y to competitively inhibitauthentic PPARγ agonist (e.g. rosiglitazone) dependent differentiationof mouse 3T3L-1 pre-adipocytes (immature fat cells) into lipid loadedmature adipocytes (mature fat cells).

FIG. 3: Illustrates the ability of Compound Y to competitively inhibitauthentic PPARγ agonist (e.g. rosiglitazone) dependent activation ofsecreted alkaline phosphatase (SEAP) reporter gene expression in primatekidney cells CV-1.

FIG. 4: Illustrates the ability of Compound Y to dose dependentlystimulate PPARα dependent SEAP reporter gene activity in human livercell line HepG2 (this cell line shows significant amounts of PPARα) witha stably integrated PPARα dependent SEAP reporter.

DETAILED DESCRIPTION OF THE INVENTION

PPARγ is a principal regulator of pre-adipocyte recruitment anddifferentiation into mature adipocytes (see Tontonoz et al., CurrentBiology, 571-576, 1995). Activators of PPARγ promote pre-adipocytedifferentiation, lipid storage in mature adipocytes and act as insulinsensitizing anti-diabetic agents (see Tontonoz et al., Current Biology,571-576, 1995; Lehmann et al., J. Biol. Chem., 270: 12953-12956, 1995;Nolan et al. New. Eng. J. Med., 331: 1188-1193; Inzucchi et al., NewEng. J. Med., 338: 867-872, 1998, Willson, et al., J. Med. Chem.: 43:527-550, 2000, Kersten et al., Nature, 405: 421424, 2000). The PPARγinduced anti-diabetic activity is however, frequently accompanied bysome body weight gain in animal models and in humans. Recent findingssuggest that that inhibition of PPARγ will lead to a reduction inadiposity and obesity (see Vidal-Puig et al., J. Clinical Investigation,99: 2416-2422, 1997; Deeb et al Nature Genetics, 20:284-287, 1998;Kubota et al. Mol. Cell; 4:597-609, 1999; Barroso et al. Nature; 402,860-861, 1999). However, such a reduction is likely to lead to higherplasma free fatty acids and hyperlipidemia and development fatty liverand insulin resistance. The PPARα isoform regulates genes in the fattyacid synthesis, fatty acid oxidation and lipid metabolism pathways (seeIssenman and Green, Nature, 347: 645-649, 1990; Torra et al., CurrentOpinion in Lipidology, 10: 151-159, 1999; Kersten et al., Nature, 405:421424, 2000). PPARα agonist (such as fenofibrate, gemfibrozil)treatment enhances fatty acid oxidation in the liver and muscle, reducesfatty acid and triglyceride synthesis in the liver, reduces plasmatriglycerides (see Kersten et al., Nature, 405: 421424, 2000). Inpatients with high triglycerides and low HDL-cholesterol treatment withPPARα agonists leads to an increase in plasma HDL-cholesterol, decreasein plasma triglycerides and reduction of both 1° and 2° cardiac events(see Balfour et al., Drugs. 40: 260-290, 1990; Frick et al., New Eng. J.Med., 317: 1237-1245; Rubins et al., New Eng. J. Med., 341: 410 -418,1999). Therefore, by combining PPARγ antagonist activity and PPARαagonist activity in a single dual acting compound or a combination of aPPARγ antagonist and a PPARα agonist it is possible to safely inhibitPPARγ and treat obesity without causing hyperlipidemia, fatty liver andinsulin resistance.

Compound Y is a compound synthesized by the scheme outlined in Example 1herein. As illustrated in FIG. 1-A, 1-B, Compound Y potently bound tohuman PPARγ ligand binding domain with high affinity (IC₅₀=69 nM).Similarly, Compound Y also potently bound to purified human PPARα ligandbinding domain (IC₅₀=69 nM). In related PPARγ ligand binding studies,the IC₅₀=250 nM for rosiglitazone (an authentic PPARγ agonist) and theIC₅₀=280 nM for GW0072 (an authentic PPARγ antagonist) were obtained. InPPARα ligand binding studies, the IC₅₀=410 nM for GW-2331 (a PPARαselective agonist) was obtained. The in vitro ligand binding studieswith purified ligand binding domain thus show the ability of Compound Yto bind potently to both PPARγ and PPARα. It is however, well known forthe nuclear hormone receptor family of transcription factors that (PPARsare members of this family) that a compound which potently binds to(i.e. a ligand) can act as an agonist (ligand which activates) and anantagonist (ligand which inactivates the receptor).

As illustrated in FIG. 2, Compound Y when added to mouse pre-adipocytecells 3T3L-1 shows competitive inhibition of rosiglitazone (a PPARγagonist) induced differentiation into mature lipid loaded adipocytes (asmeasured by glycerol release from the cells). Mouse 3T3-L-pre-adipocyteshave been known to respond to hormonal signals (such as insulin,dexamethazone) and PPARγ agonists (such as rosiglitazone) anddifferentiate into mature adipocytes and accumulate lipids. PPARγ hasbeen considered a major trigger for the adipocyte differentiationprocess (see Tontonoz et al., Current Biology, 571-576, 1995). Although,Compound Y is a potent ligand for PPARγ, it shows competitive inhibitionof rosiglitazone induced differentiation, suggesting therefore that itis an antagonist of PPARγ. The ED₅₀ for inhibition ofdifferentiation=9.9 μM shows Compound Y is a moderate inhibitor ofpre-adipocyte differentiation. In comparison the ED₅₀=0.585 μM wasobtained for GW0072, an PPARγ antagonist ((see Oberfield et al, Proc.Nat. Acad. Sci., 96: 6102-6106, 1999).

As illustrated in FIG. 3 the PPARγ antagonist activity of Compound Y wasverified in a second cell line. The established CV-1 cells (primatekidney origin), that show expression of endogenous PPARγ, were stablytransfected with a PPAR responsive secreted alkaline phosphatase (SEAP)reporter gene. As with previous study, Compound Y was competitivelyinhibited rosiglitazone (a PPARγ agonist) dependent activation, namelyinduction of SEAP reporter gene expression in CV-1 cells. The ED₅₀=1.5μM for specific inhibition of rosiglitazone induced transactivation ofSEAP gene shows once again, Compound Y is an antagonist of PPARγ. In thestudy GW0072, a PPARγ antagonist (see Oberfield et al, Proc. Nat. Acad.Sci., 96: 6102-6106, 1999) also dose dependently inhibited rosiglitazonemediated induction of SEAP gene in CV-1 cells with an ED₅₀=0.37 μM forinhibition and verified the reliability of data.

As illustrated in FIG. 4 Compound Y dose dependently stimulated PPARαdependent transactivation of SEAP reporter gene in human liver cellsHepG2, showing thereby that it is an agonist of PPARα. HepG2 cells(human liver origin), that express endogenous PPARα gene were stablytransfected with a PPAR responsive SEAP reporter gene. Upon treatment,Compound Y dose dependently stimulated SEAP gene expression in HepG2cells with an EC₅₀ for PPARα transactivation=0.587 μM. In this studyBMS-250773 (a PPARα selective agent) dose dependently stimulated PPARαdependent transactivation of SEAP reporter gene with an EC₅₀=0.063 μMand rosiglitazone (a PPARγ agonist) showed very little activation.

Thus, the in vitro PPARγ and PPARα ligand binding studies and PPARγ andPPARα dependent cell based transactivation studies described in FIGS. 1,2, 3,4 show Compound Y is a potent ligand for both PPARγ and PPARα,however, it shows antagonist activity towards PPARγ and agonist activitytowards PPARα. These findings indicate Compound Y belongs to a novelclass of molecules which possess both (dual) PPARγ antagonist activityand PPARα agonist activity in a single molecule. TABLE 1 BMS- Compound YGene compound C Dual expression Rosiglitazone Dual α/γ γ antagonist/Comments/Likely in WAT γ agonist agonist α agonist outcome HMGic NC NC2.2 PPAR γ antagonist effect Reduced adipocyte differentiationGlycerol-3 NC NC  0.39 PPAR γ antagonist PO4 effect dehydrogenaseReduced adipocyte differentiation Fatty acid 2.5 3.7 NC PPAR γantagonist transport effect protein No change in FA transport into cellG-protein 4.3 19.2  NC PPAR γ antagonist coupled effect receptor Play arole in 26 adipocyte differentiation Adipophilin NC 9.6 4.1 PPAR αagonist effect Increased FA mobilization in cytoplasm Keratinocyte NC2.6 3.3 PPAR α agonist effect fatty Increased FA retention acid incytoplasm binding protein

As illustrated in Table 1, Compound Y shows both PPARγ antagonist andPPARα agonist effects at the level of expression of several genes invivo. In order to demonstrate the in vivo PPARγ antagonist and PPARαagonist effect of Compound Y, obese diabetic db/db mice were treatedwith Compound Y, rosiglitazone (an authentic PPARγ agonist) andBMS-compound C (this compound possess agonist activity towards bothPPARα and PPARγ. At the termination of the study white adipose tissue(WAT) was harvested, total RNA prepared and analyzed for effect ontarget gene expression. These analyses demonstrated that a number ofgenes whose expression is specifically altered by Compound Y treatmentand confirmed the in vivo PPARγ antagonist activity of Compound Y. Forexample expression of (1) HMGic which prevent adipocyte differentiationis induced by Compound Y and not by rosiglitazone or BMS-compound C, (2)glycerol3-PO₄ dehydrogenase which promote adipocyte differentiation isinhibited by Compound Y and not by rosiglitazone and BMS-compound C, (3)fatty acid transport protein which promote fatty acid transport into thecell remained unaffected by Compound Y was, however, induced byrosiglitazone and BMS-compound C and (4) an orphan GPCR 26 which isrelated to the bombesin receptor remained unaffected by Compound Y wasinduced by rosiglitazone and BMS-compound C. These analyses alsodemonstrated a number of other genes whose expression is induced only byCompound Y and BMS-compound C and not by rosiglitazone confirming PPARαagonist activity of Compound Y in vivo. Examples of such genes includeadipophilin and keratinocyte fatty acid binding protein, the geneproducts of these genes are involved in intracellular fatty acidtrafficking).

Thus the gene expression profiling studies confirm the in vivo PPARγantagonist and PPARα agonist activity of the dual PPARγ antagonist/PPARαagonist Compound Y. Furthermore, these studies also show a method fortreating obesity by changing genes which affect adipocytedifferentiation such as HMGic, glycerol 3-PO₄ dehydrogenase, fatty acidtransport protein and the novel orphan G-protein coupled receptor 26levels, in adipose (fat) tissue through administration of PPARγantagonists and or dual PPARγ antagonist/PPARα agonists. These studiesalso show a method for treating obesity by changing adipophilin andkeratinocyte fatty acid binding protein levels in adipose (fat) tissuethrough administration of PPARα agonist and or dual PPARγantagonist/PPARα agonist. TABLE 2 Comments/ BMS- Compound Y Likelyoutcome Gene compound C Dual γ of expression in Rosiglitazone Dual α/γantagonist/ PPARγ antagonist WAT γ agonist agonist α agonist effectPAI-1 NC NC 0.45 PPAR γ antagonist effect Reduced risk for thrombosisAngiotensinogen NC NC 0.46 PPAR γ antagonist precursor effect Lowerangiotensinogen I/II level Reduced risk for hypertension Renin 13.9 2.1NC PPAR γ agonist effect No change in angiotensinogen I/II level Nochange in risk for hypertension

As illustrated in Table 2, expression profiling analysis of whiteadipose tissue (WAT) of obese diabetic db/db mice treated with dualPPARγ antagonist/PPARα agonist Compound Y shows substantial beneficialchanges in the expression of several genes which are known to play arole in the development of cardiovascular disease. Adipose (fat) tissueis a major place of synthesis of PAI-1, a risk factor for thrombosis,angiotensinogen precursor, a risk factor for hypertension and renin, arisk factor for hypertension (see Ahima and Flier, TEM, 11: 327-332,2000). The inhibition of PAI-1 and angiotensinogen precursor geneexpression and absence of a change in the expression of renin gene,selectively with Compound Y confirms once again the PPARγ antagonistactivity, and shows the cardiovascular beneficial effects of treatmentof obese mammals including human with a dual PPARγ antagonist/PPARαagonist such as Compound Y. TABLE 3 Free fatty Glucose Triglycerideacids Treatment (mg/dL) (mg/dL) (meq/L) Vehicle 780.9 ± 43.8 265.2 ±34.3 1.18 ± 0.06 Compound Y 683.0 ± 25.2 145.3 ± 12.5 0.76 ± 0.12 (3mg/kg/day) 13% −45%* −36%**p < 0.05

As illustrated in Table 3 treatment of obese diabetic db/db mice withthe dual PPARγ antagonist/PPARα agonist Compound Y results in nosignificant change in plasma glucose and a significant decrease inplasma triglycerides and free fatty acids levels. As indicated before,changes in lipid and glycemic conditions are two significant potentialconcerns of reducing PPARγ activity. Based on the study described hereit is concluded that obese mammals can be safely treated with a dualPPARγ antagonist/PPARα agonist. The reduction in plasma triglyceridesand free fatty acids are likely due to the PPARγ agonist activity ofCompound Y. TABLE 4 Treatment % Fat body mass % Lean body mass Vehicle47.2 ± 1.5 50.5 ± 1.4 Compound Y 41.5 ± 1.8 56.0 ± 1.8 (10 mg/kg/day)(−12%)* (+11%)**P < 0.05

As illustrated in Table 4, treatment of diet induced obese mice withdual PPARγ antagonist/PPARα agonist Compound Y for 3 weeks at 10mg/kg/day, once a day resulted in a significant 15% reduction of bodyfat mass and a corresponding 14% increase in lean body mass indicatingto the beneficial effect of Compound Y. Reduction in fat mass upontreatment with dual PPARγ antagonist/PPARα agonist Compound Y is mostlikely due to the result of inhibition of PPARγ activity leading toreduced adipocyte (fat cell) expansion and reduced accumulation of fatmass. Although, no significant reduction in body weight is observed inthis study, reduced fat mass and compensating increase in lean body mass(such a compensation is not observed in human lipodystrophic patientswith defects in fat tissue accumulation) represent a significantbeneficial effect of treatment with dual PPARγ antagonist/PPARα agonistCompound Y. It is possible that PPARα agonist activity contributes tothe increase in lean muscle mass build up, possibly through induction offatty acid metabolism pathway genes and or through induction muscleprotein synthesis by an unknown mechanism. TABLE 5 CholesterolTriglyceride Glucose Insulin Treatment (mg/dL) (mg/dL) (mg/dL) (ng/ml)Vehicle 281.8 ± 26.5  95.1 ± 7.2 241.4 ± 12.8 9.7 ± 1.5 Compound Y 270.4± 9.4  105.5 ± 8.1 260.7 ± 12.3 8.2 ± 1.2 (10 mg/kg/day)

As illustrated in Table 5 treatment of diet induced obese mice with thedual PPARγ antagonist/PPARα agonist Compound Y resulted in very littlechange in plasma lipid (free fatty acids, triglycerides and cholesterol)and glycemic (glucose and insulin) parameters. As indicated before,changes in lipid and glycemic conditions are two potential concerns ofreducing PPARγ activity. Based on the study described here it isconcluded that safe reduction of fat mass in an obese diabetic mammal(including human) is possible through administration of a dual PPARγantagonist/PPARα agonist. This feature is in contrast to the observedhyperlipidemia and hyperglycemia in lipodystrophic patients and inpatients with severe mutations in PPARγ gene. TABLE 6 Livertriglycerides ALT Treatment (mg/g) (IU/L) Vehicle 72.5 ± 4.8 158.8 ±20.2 Compound Y 55.4 ± 7.0  98.0 ± 12.6 (10 mg/kg/day) (−24%) (−38%)**P < 0.05

As illustrated in Table 6, treatment of diet induced obese mice with thedual PPARγ antagonist/PPARα agonist Compound Y results in an improvementin liver phenotype. In obese mice, as in obese human, the liver lipidlevel is elevated. Often, this is accompanied by an increase in plasmaliver enzyme ALT level indicating to liver damage. Upon treatment withdual PPARγ antagonist/PPARα agonist Compound Y there was a substantialreduction in liver triglyceride content, although not reachingstatistical significance, which was accompanied by a significantreduction in plasma liver enzyme ALT levels. Both these changes areindicative of improvement in liver function as a result of stimulationof PPARα mediated fatty acid oxidation and reduction of lipid synthesisleading to reduced lipid content (see. Torra et al., Current Opinion inLipidology, 10: 151-159, 1999; Kersten et al., Nature, 405: 421424,2000).

The present invention therefore shows the discovery of a novel dualacting PPARγ antagonist/PPARα agonist agent. This invention provides apharmacological proof of principle for treating obesity through theadministration of a dual PPARγ antagonist/PPARα agonist. In accordancewith this invention, combining PPARγ antagonist activity and PPARαagonist activity in a single molecule or combining PPARγ antagonistactivity and PPARα agonist activity in a medicament, will offertreatment of obesity without any further deterioration of lipid and orglycemic control in obese individuals.

This invention presents the identity of a list of genes whose expressionis modified to achieve anti-obesity (such as HMGic, glycereol-PO₄dehydrogenase, fatty acid transport protein, G-protein coupled receptor26, adipophilin, keratinocyte fatty acid binding protein) andcardiovascular (such as angiotensinogen, PAI-1, renin) benefits throughtreatment by a PPARγ antagonist, or a dual PPARγ antagonist/PPARαagonist or a PPARα agonist.

This invention also presents a method for treating liver dysfunctionthrough the administration of a dual PPARγ antagonist/PPARα agonist orPPARα agonist.

The present invention also provides a method for treating obesity, inmammals, including human, through administration of a pharmacologicalcomposition containing a single agent or a combination of two agentswhich will simultaneously reduce: (1) the activity of PPARγ protein, or(2) expression of the PPARγ gene, (3) binding of a co-activator or (4)expression of PPARγ regulated target genes (or any combination of theabove) and increase (1) the activity of PPARα protein, or (2) expressionof the PPARα gene, or (3) binding of a co-activator or (4) expression ofPPARα regulated target genes (or any combination of the above). Theresulting product of these changes may include any combination of (butare not limited to): (1) prevention of weight gain, (2) weight loss, (3)specific reduction fat mass, (4) increase in lean body mass (5) changein body fat mass/lean mass ratio, (7) reduction of liver lipid andimprovement in liver function.

The present invention also provides a treatment method involving the useof a combination of a dual PPARγ antagonist/PPARα agonist withanti-diabetic agents such as but not limited to metformin, sulfonylurea,insulin, insulin sensitizers, aP2 inhibitor, SGLT2 inhibitor, agentsthat affect liver glucose output, a lipid lowering agent such as a PPARαagonist (such as but not limited to fenofibrate and gemfibrozil) and aHMG-COA reductase inhibitor (such as, but not limited to, pravastatin,lovastatin, simvastatin and atorvastatin), niacin, ACT inhibitors, LCATactivators, bile acid sequestering agents and other anti-obesity agents(such as, but not limited to, orlistat, sibutramine, aP2 inhibitor,adiponectin) to control body weight, insulin resistance, Type 2diabetes, hyperlipidemia and cardiovascular diseases in obese patients.

The compounds of the formula I of the present invention may be preparedaccording to the following general synthetic schemes, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working Examples. Protection and deprotection inthe Schemes below may be carried out by procedures generally known inthe art (see, for example, Greene, T. W. and Wuts, P. G. M., ProtectingGroups in Organic Synthesis, 3^(rd) Edition, 1999 [Wiley]).

The synthesis of key intermediates required for the synthesis of thecompounds of the invention are described in Scheme 1. An alcohol 1(R⁵(CH₂)_(x) ²OH) (of which one of the most favored is2-phenyl-5-methyl-oxazole-4-ethanol) is coupled with a hydroxy aryl- orheteroaryl- aldehyde 2 under standard Mitsunobu reaction conditions(e.g. Mitsunobu, O., Synthesis, 1981, 1) to furnish the key intermediatealdehyde 3. Alternatively, the alcohol 1 can be converted to itsmethanesulfonate ester 4 under standard conditions; the mesylate 4 canthen be used to alkylate the hydroxy aryl- or heteroaryl- aldehyde 2 tofurnish the aldehyde 3.

Scheme 2 describes a general synthesis of 2-aryl (heteroaryl)4-carboxy-triazoles I. Treatment of a suitably protected oxybenzoic oroxyphenylacetic acid chloride 5 with Meldrum's acid in the presence ofbase provides the corresponding crude Meldrum's acid adduct 6 which isimmediately reacted with aniline to give the β-keto anilide 7(Synthesis, 1992, 1213-1214). The β-keto amide 7 is reacted with nitrousacid (generated in situ from base/sodium nitrite) followed by acidtreatment to furnish the corresponding α-oxime β-keto amide 8(Reference: Hamanaka, E. S., et al, WO9943663). The β-keto-amide 8 isthen condensed with an appropriately substituted hydrazine 9 to providethe corresponding β-hydrazone-amide 10. Treatment of intermediate 10with acid furnishes the desired 2-substituted 4-carboxamido-triazole 11(Reference: Hamanaka, E. S., et al, WO9943663). Deprotection of thephenolic protecting group of triazole-anilide 11 furnishes thecorresponding phenol 12. The phenol-triazole 12 is then coupled with anappropriate alcohol 1 under standard Mitsunobu reaction conditions (e.g.Mitsunobu, O., Synthesis, 1981, 1) to furnish the desired alkylatedtriazole-amide 13. Alternatively, the phenol can be coupled with themethanesulfonate ester 4 under basic conditions to furnish the alkylatedtriazole-amide 13 (Reference: Cheng, P. T. W., et. al., WO0121602).Subsequent base-mediated deprotection of this anilide furnishes thedesired 2-substituted 4-carboxy triazole II of the invention.

Scheme 3 illustrates a complementary approach to that shown in Scheme 2for the preparation of 2-aryl 4-carboxy triazoles I. An appropriatelyprotected hydroxyaryl or hydroxyheteroaryl carboxylic acid 14 is treatedeither with: 1) mesylate 4 in the presence of base or 2) alcohol 1 understandard Mitsunobu conditions to furnish, after deprotection of thecarboxylic acid, the key alkylated acid intermediate 15. Conversion ofacid 15 to the corresponding acid chloride 16 is achieved using oxalylchloride. Treatment of acid chloride 16 with Meldrum's acid furnishesthe corresponding adduct 17, which is then immediately reacted withaniline to provide the β-keto anilide 18. Treatment of the β-ketoanilide 18 with nitrous acid (generated in situ from base/NaNO₂) thenfurnishes the corresponding β-keto α-oximino-anilide 19, which is thenreacted with an appropriately substituted hydrazine 9 to provide theintermediate β-hydrazone-amide 20. Acid-mediated cyclization of theoxime-hydrazone 20 then gives the aryltriazole anilide 21. Finally,base-mediated hydrolysis of the anilide furnishes the desired2-substituted 4-carboxytriazole IIA of the invention.

Scheme 4 describes the synthesis of 1-substituted 4-carboxytriazoles II.Treatment of β-keto anilide 18 with p-toluenesulfonyl azide (Padwa, A.,et al, J. Org. Chem., 1997, 62, 6842) furnishes the corresponding β-ketoα-diazo-anilide 21. Lewis acid-mediated reaction of the β-ketoα-diazo-anilide 21 with an appropriately substituted amine 22 furnishesthe corresponding 1-substituted-4-amido triazole 23 (Ohno, M., et al,Synthesis, 1993, 793). Deprotection of the phenol functionality oftriazole-anilide 23 furnishes the phenol 23. Alkylation of thephenol-triazole 23 is then achieved with alcohol 1 under standardMitsunobu reaction conditions (e.g. Mitsunobu, O., Synthesis, 1981, 1)to furnish the corresponding alkylated triazole-amide. Alternatively,the phenol-triazole 23 can be coupled with the methanesulfonate ester 4under basic conditions to furnish the same alkylated triazole-amide.Subsequent base-mediated deprotection of carboxylic acid furnishes thedesired 1-substituted-4-carboxy triazole III of the invention.

Scheme 5 describes the synthesis of the regioisomeric1-substituted-5-carboxy triazoles III and 1-substituted-4-carboxytriazoles IV. Aldehyde 3 is reacted with an appropriately protectedpropargylic acid under basic/anionic conditions (J. Org. Chem., 1980,45, 28) to furnish the corresponding acetylenic alcohol adduct 25. Theacetylenic alcohol 25 is then deoxygenated under standard literatureconditions (Czernecki, S., et al, J. Org. Chem., 1989, 54, 610) to givethe acetylenic ester 26. Dipolar cycloaddition of the acetylenic ester26 with an appropriately substituted aryl azide 27 under thermalconditions (Can. J. Chem., 1980, 58, 2550) furnishes, after deprotectionof the carboxylic acid functionality, the desired aryl triazole acids IVand V of the invention.

Scheme 6 shows a slightly altered sequence for the preparation oftriazole acids IV and V as well as the hydroxy triazole acids VI andVII. The acetylenic alcohol adduct 25 can immediately undergo thedipolar cycloaddition reaction with the appropriately substituted azide27 under thermal conditions to give the corresponding regioisomerichydroxy triazole esters 28 and 29, which are then deprotected to providethe hydroxy triazole acids VI and VII respectively, of the invention.Alternatively, the hydroxy triazole esters 28 and 29 undergodeoxygenation and deprotection reactions to furnish the triazole acidsIV and V of the invention.

Scheme 7 describes the synthesis of 1-substituted 4-carboxypyrazolesVIII. A protected phenol-alcohol 30 is converted to the correspondingchloride 31 by standard literature methods (Tetrahedron Lett., 1986, 42,2725). A protected cyanoacetate 32 is then alkylated with chloride 31 inthe presence of base to provide the cyanoacetate 33. Deprotection of thecyanoacetate 33 furnishes the cyanoacetic acid 34. Treatment ofcyanoacetic acid 34 with an appropriately substituted hydrazine 9 in thepresence of nitrous acid (generated in situ from sodium nitrite andacid) provides the corresponding cyano-hydrazone 35 (Skorcz, J. A., etal, J. Med. Chem., 1966, 9, 656). Reaction of cyano-hydrazone 35 with anappropriately protected acrylate 36 in the presence of base (Kim, Y. H.,et al, Tetrahedron Lett., 1996, 37, 8771) gives the key aryl-pyrazoleester intermediate 37. A three-step sequence involving: 1) removal ofthe phenolic protecting group of pyrazole 37, 2) alkylation of theresulting phenol with mesylate 4 under basic conditions and 3)deprotection of the carboxylic acid furnishes the 1-aryl 3-substituted4-carboxypyrazole VIII of the invention.

Scheme 8 illustrates the synthesis of the regioisomeric 1-substituted5-substituted 4-carboxypyrazoles IX. The protected phenol-acid chloride5 is treated with Meldrum's acid under basic conditions to give thecorresponding adduct, which is reacted with an appropriate alcohol R₃OHto provide the β-ketoester 38. Treatment of the β-keto-ester 38 withdimethyl formamide dimethyl acetal (Almansa, C., et al, J. Med. Chem.,1997, 40, 547) gives the α-enamino-β-keto-ester 39. Reaction of theα-enamino-β-keto-ester 39 with an appropriately substituted hydrazine 9followed by intramolecular cyclization furnishes the aryl-N-pyrazoleester 40. A three step sequence: 1) removal of the phenolic protectinggroup of 40, 2) alkylation of the resulting phenol with mesylate 4 and3) deprotection of the carboxylic acid furnishes the N-substitutedpyrazole acid IX of the invention.

A synthesis of the regioisomeric carboxypyrazoles X is shown in Scheme9. Treatment of aldehyde 3 (with an appropriately substitutedalkynylmetal reagent 41) furnishes the acetylenic alcohol adduct 42.Alcohol 42 is then treated with ketene dimer under thermal conditions(Kato, T., et al, Chem. Pharm. Bull., 1975, 20, 2203) to provide theacetoacetate ester 43. Chlorination of acetoacetate ester 43 understandard conditions (reference) furnishes the α-chloro, β-ketoester 44.Treatment of the α-chloro, β-ketoester 44 with an appropriatelysubstituted diazo compound 45 under thermal conditions furnishes thechlorohydrazone 46 (Garantic, L., et al, Synthesis, 1975, 666).Base-mediated thermal intramolecular cycloaddition of chlorohydrazone 46(Garantic, L., et al, Synthesis, 1975, 666) then furnishes thepyrazole-lactone 47. Concomitant ring-opening/deoxygenation of thepyrazole-lactone 47 is achieved under a number of different reactionconditions (TMSCl/NaI or Zn/NH₄OH; Sabitha, G., Synth. Conmuun., 1998,28, 3065) to furnish the pyrazole acid 48. A three step sequence: 1)removal of the phenolic protecting group of 48, 2) alkylation of theresulting phenol with mesylate 4 and 3) deprotection of the carboxylicacid furnishes the N-substituted pyrazole acids X of the invention.

A general route to the N-substituted pyrrole 3-carboxylic acids XI isshown in Scheme 10. The aldehyde 3 is reacted under basic conditionswith an appropriately protected propiolate ester 49 ((J. Org. Chem.,1980, 45, 28) to provide the alkyne-alcohol 50. Deoxygenation of thealcohol functionality of alkyne 50 using standard methods (e.g.Et₃SiH/acid; Tetrahedron Lett., 1987, 28, 4921) provides the alkynoateester 51. Reduction of the alkynoate ester 51 using standard methods(“Preparation of Alkenes, A Practical Approach”, J. M. J. Williams, Ed.,Chapter 6, “Reduction of Alkynes”, J. Howarth. Oxford University Press,1996) furnishes the Z-alkenyl ester 52. The α,β unsaturated ester 52 isthen reacted with tosylmethyl isocyanate (TosMIC) under standardliterature conditions (Van Leusen, A. M., et al, Tetrahedron Lett.,1972, 5337) to give the corresponding pyrrole-ester 53. Coupling of thepyrrole-ester 53 with an appropriately substituted aryl or heteroarylboronic acid 54 using standard literature conditions (Lam, P. Y. S., etal, Tetrahedron Lett., 1998, 39, 2941) furnishes the N-substitutedpyrrole ester 55. Deprotection of the N-substituted pyrrole ester 55then provides the N-substituted pyrrole acid XI of the invention.

Scheme 11 illustrates a synthetic route to N-substituted pyrrole3-carboxylic acids XII. The aldehyde 3 undergoes a Wittig reaction witha phosphoranylidene ester 53 (“Preparation of Alkenes, A PracticalApproach”, J. M. J. Williams, Ed., Chapter 2, “The Wittig reaction andrelated methods”, N. J. Lawrence, Oxford University Press, 1996) or aHorner-Emmons reaction with a phosphonate ester 56 (J. M. J. Williams,supra and N. J. Lawrence, supra) to give the predominantly E-alkenylester 57. The E-alkenyl ester 57 is then reacted with tosylmethylisocyanate (TosMIC) to provide the pyrrole-ester 58. Pyrrole-ester 58 isthen reacted with appropriate boronic acid 54 under standard literatureconditions (Evans reference) to provide the corresponding N-substitutedpyrrole ester 59. Deprotection of N-substituted pyrrole ester 59 thengives the N-substituted pyrrole acid XII of the invention.

Scheme 12 shows the preparation of the required intermediate 2-aryl (or2-heteroaryl)-5-methyl-oxazol-4-yl methyl chloride (following thegeneral procedure described in Malamas, M. S., et al, J. Med. Chem.,1996, 39, 237-245). A substituted aldehyde 60 is condensed withbutane-2,3-dione mono-oxime under acidic conditions to give thecorresponding oxazole N-oxide 61. Deoxygenation of the oxazole N-oxide61 with concomitant chlorination furnishes the desired chloromethyl aryl(or heteroaryl)-oxazole 62. Hydrolysis of chloromethyl oxazole 62 underbasic conditions furnishes the corresponding oxazole-methanol 63.Oxidation of alcohol 63 to the corresponding aldehyde is followed byconversion to the corresponding dibromoalkene 64 (e.g. Ph₃P/CBr₄). Thedibromide 64 is converted to the corresponding alkynyl-lithium species(using an organolithium reagent such as n-BuLi), which can be reacted insitu with an appropriate electrophile such as formaldehyde to give thecorresponding acetylenic alcohol (ref: Corey, E. J., et al., TetrahedronLett. 1972, 3769, or Gangakhedkar, K. K., Synth. Commun. 1996, 26,1887-1896). This alcohol can then be converted to the correspondingmesylate 65 and alkylated with an appropriate phenol 66 to provide,after deprotection of the carboxylic acid, analog XIII. In general,phenol 66 is obtained by deprotection of the phenol functionality ofappropriate intermediates such as 11, 23 and 37. Stereoselective partialreduction of alkyne XIII of the invention (e.g. H₂/Lindlar's catalyst)provides the E- or Z-alkenyl analog XIV. Complete reduction of alkeneanalog XIV (hydrogenation) provides the alkyl analog XV of theinvention. Alternatively, complete reduction (e.g. H₂/Palladium onCarbon catalyst) of alkyne analog XIII of the invention also providesthe alkyl analog XV of the invention.

The synthesis of carbon-linked analogs XVI, XVII, and XVIII are shown inSchemes 13-14. The synthetic sequence is analogous to that shown inScheme 2. Treatment of a suitably protected halo-aryl (or heteroaryl)acid chloride 67 with Meldrum's acid in the presence of base providesthe corresponding crude Meldrum's acid adduct 68 which is immediatelyreacted with aniline to give the β-keto anilide 69. The β-keto amide 69is reacted with nitrous acid (generated in situ from base/sodiumnitrite) followed by acid treatment to furnish the corresponding α-oximeβ-keto amide 70. The β-keto-amide 70 is then condensed with anappropriately substituted hydrazine 9 to provide the correspondingβ-hydrazone-amide 71. Treatment of intermediate 71 with acid furnishesthe desired 2-aryl 4-carboxamido-triazole 72. Coupling of the alkyne 73with halo-triazole 72 under standard Sonogashira reaction conditions(e.g. “Organocopper Reagents, a Practical Approach”, R. J. K. Taylor,E., Chapter, 10, p 217-236, Campbel, I. B., Oxford University Press,1994) furnishes the corresponding alkynyl triazole 74. Hydrolysis of theanilide 74 then provides the alkynyl triazole acid analog XVI of theinvention. Selective reduction of the alkynyl triazole acid XVI of theinvention (e.g. H₂/Lindlar catalyst) provides the E- or Z-alkenyltriazole acid XVII of the invention. Complete reduction of alkenyltriazole acid XVII of the invention then provides the saturated alkyltriazole acid XVIII of the invention.

The synthesis of ether-containing analogs XIX and XX are shown inSchemes 15-16.

In Scheme 15, treatment of a suitably protected halo-aryl triazole 72with a metallating agent (e.g. isopropyl magnesium bromide, reference:P. Knochel et al., Synthesis, 2002, 565-569) furnishes the correspondingarylmagnesium reagent, which is then reacted with formaldehyde toprovide benzyl alcohol 75. Treatment of alcohol 75 with mesylate VIII inthe presence of base provides the corresponding ether-anilide, which isthen deprotected to furnish the ether-acid XIX of the invention.

In Scheme 16, treatment of a suitably protected halo-aryl triazole 72with an appropriate vinyl tin reagent (e.g. tributylvinyltin) underStille coupling conditions (reference: Farina, V., Krishnamurthy, V.,and Scott, W. J., Organic Reactions, 1997, 50, 1) provides thecorresponding vinyl intermediate, which can then undergo hydroboration(e.g. borane-THF) to give the alcohol 76. Treatment of alcohol 76 withmesylate VIII in the presence of base provides the corresponding etheranilide, which is then deprotected to provide the ether acid XX of theinvention.

A synthesis of 2-substituted triazole-4-acids XXI is shown in Scheme 17.Treatment of acetylenic ester 26 with sodium azide results in a dipolarcycloaddition which provides the triazole-ester 77. Coupling of thetriazole-ester 77 with an appropriately substituted aryl or heteroarylboronic acid 54 using standard literature conditions (Lam, P. Y. S., et.al., Tetrahedron Lett., 1998, 39, 2941) furnishes preferentially theN(2)-substituted triazole ester 78. Deprotection of the triazole-ester78 then provides the N(2)-substituted triazole acid XXI of theinvention.

The syntheses of the homologated ether-containing analogs XXII-XXIV areshown in Schemes 18-19.

In Scheme 18, treatment of a suitably protected halo-aryl triazole 72with a suitably protected acetylenic alcohol 79 (where x³=1-3 ispreferred) under standard Sonogashira coupling conditions (e.g.“Organocopper Reagents, a Practical Approach”, R. J. K. Taylor, E.,Chapter, 10, p 217-236, Campbell, I. B., Oxford University Press, 1994)furnishes the corresponding alkynyl triazole 80. Hydrogenation of 80followed by deprotection of the alcohol provides the triazole-alcohol81. Treatment of alcohol 81 with mesylate VIII in the presence of baseprovides the corresponding ether-anilide, which is then deprotected tofurnish the ether-acid XXII of the invention.

In Scheme 19, deprotection of triazole 80 furnishes the acetylenicalcohol 81, which undergoes reaction with mesylate VIII in the presenceof base to provide the corresponding ether anilide, which is thendeprotected to provide the ether acid XXIII of the invention. Selectivereduction of the alkynyl triazole acid XXIII (e.g. H₂/Lindlar catalyst)provides the E- or Z-alkenyl triazole acid XXIV of the invention.

These general synthetic schemes for the preparation of triazole-acidanalogs are also applicable to pyrrole-acid analogs, as shown in Schemes20-21. The synthetic scheme for the preparation of pyrrole acid analogsXXV-XXIX follows the approach described in Scheme 10. The halo-aldehyde83 is reacted under basic conditions (most preferably with fluorideanion in the presence of 18-crown-6) with a trimethylsilylpropiolateester 84 to provide the alkyne-alcohol 85. Deoxygenation of the alcoholfunctionality of alkyne 50 using standard methods (e.g. Et₃SiH/acid;Tetrahedron Lett., 1987, 28, 4921) provides the alkynoate ester 86.Reduction of the alkynoate ester 86 using standard methods (“Preparationof Alkenes, A Practical Approach”, J. M. J. Williams, Ed., Chapter 6,“Reduction of Alkynes”, J. Howarth. Oxford University Press, 1996)furnishes the Z-alkenyl ester 87. The α,β-unsaturated ester 87 is thenreacted with tosylmethyl isocyanate (TosMIC) under standard literatureconditions (Van Leusen, A. M., et al, Tetrahedron Lett., 1972, 5337 ) togive the corresponding pyrrole-ester 88. Coupling of the pyrrole-ester88 with an appropriately substituted aryl or heteroaryl boronic acid 54using standard literature conditions (Lam, P. Y. S., et al, TetrahedronLett., 1998, 39, 2941) furnishes the key intermediate, halo-arylN-substituted pyrrole ester 89, which is the pyrrole equivalent of thehalo-aryl triazole intermeidate 72. Subjection of the haloaryl pyrrole89 to the same reaction sequences as described in Schemes 15, 16, 18 and19 for triazole 72 provides the pyrrole acids XXV-XXIX of the inventionas shown in Scheme 21.

The synthesis of homologated triazole acids XXX is shown in Scheme 22and follows a modified Arndt-Eistert protocol (ref. E. Gordon et al., J.Med. Chem., 1988, 31, 2199). Treatment of triazole-acid IIA with oxalylchloride provides the corresponding acid chloride, which is immediatelyreacted with diazomethane to provide the corresponding α-diazoketone 90.Treatment of diazoketone 90 with a silver salt (e.g. silver benzoate) inthe presence of methanol affords the corresponding homologated triazoleester. Hydrolysis of the triazole-ester furnishes the desiredhomologated triazole-acids XXX.

The synthesis of homologated pyrrole-acids XXXI is shown in Schemes23-24. Coupling of protected aryl halide 91 with the silyl-alkyne 92under standard Sonogashira conditions (ref. Organocopper Reagents, aPractical Approach, R. J. K. Taylor, Ed., Chapter 10, pp 217-236,Campbell, I. B., Oxford University Press, 1994) provides the arylalkyne93. Removal of the silyl group (e.g. fluoride) followed by treatmentwith base and an appropriate chloroformate 94 (e.g. methylchloroformate) furnishes the alkynoate ester 95. 1,3-Dipolarcycloaddition of acetylenic ester 95 with N-trimethylsilylmethylN-methoxymethyl benzylamine 96 under standard literature conditions(e.g. J. S. Carey, J. Org. Chem., 2001, 66, 2526-2529) furnishes theN-benzyl dihydropyrrole 97. Selective deprotection of the N-benzyl groupunder standard literature conditions (R. A. Olofson et al, J. Org.Chem., 1984, 49, 2081) provides the dihydropyrrole 98, which is thenreprotected (e.g. PG₃ as the t-butyloxy carbamate or as the benzyloxycarbamate) as intermediate 99. Reduction of dihydropyrrole ester 99 bystandard literature methods (e.g. diisobutylaluminum hydride) furnishesthe corresponding allylic alcohol, which then undergoes halogenation bystandard literature methods (e.g. Ph₃P/CBr₄ or PBr₃ to furnish thebromide; Ph₃P/CCl₄ to furnish the chloride) furnishes the correspondingallylic halide 100. Carbonylation (ref. Kiji, J. et al, Bull. Chem. Soc.Jpn., 1996, 69, 1029-1031) with carbon monoxide in the presence of apalladium catalyst and methanol) of 100 provides the dihydropyrroleester 101, which is deprotected to afford amine 102. Reaction of 102with boronic acids 54 in the presence of a copper (I) salt and base withheating furnishes the pyrrole-ester 103. Deprotection of the phenol of103 is carried out by treatment with boron tribromide followed byalkylation with mesylate 4 under basic conditions provides the pyrroleester 104. Deprotection of pyrrole-ester 104 by hydrolysis thenfurnishes the homologated pyrrole-acids XXXI of the invention.

An alternative synthesis of triazole acids IIA is shown in Scheme 25.Treatment of β-ketoester 38 with a diazonium salt 105 provides thediazo-β-ketoester 106 (ref: V. S. Jolly et al, J. Indian Chem. Soc.,1991, 68, 513-514). Reaction of diazo-β-ketoester 106 with a copper (II)salt such as copper (II) acetate under elevated temperatures (ref: F.Zumstein et al, German patent DT2133012, 1970) furnishes the triazoleester 107. A 3-step sequence comprising: 1) deprotection of the phenolmoiety of triazole ester 107 for example by treating with borontribromide; 2) alkylation of the phenol with mesylate 4 under basicconditions and 3) deprotection of the acid for example by hydrolysis,then provides the desired triazole-acids IIA.

In this and the following Reaction Schemes, R⁵=

Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” asemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons, containing 1 to 20 carbons, preferably1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain,and may optionally include an oxygen or nitrogen in the normal chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1 to 4 substituents such as halo, for example F, Br, Cl or Ior CF₃, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy,cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl,heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/oralkylthio and/or any of the R³ groups.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl andtricyclicalkyl, containing a total of 3 to 20 carbons forming the rings,preferably 3 to 10 carbons, forming the ring and which may be fused to 1or 2 aromatic rings as described for aryl, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyland cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/orany of the substituents for alkyl.

The term “cycloalkenyl” as employed herein alone or as part of anothergroup refers to cyclic hydrocarbons containing 3 to 12 carbons,preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may beoptionally substituted as defined for cycloalkyl.

The term “cycloalkylene” as employed herein refers to a “cycloalkyl”group which includes free bonds and thus is a linking group such as

and the like, and may optionally be substituted as defined above for“cycloalkyl”.

The term “alkanoyl” as used herein alone or as part of another grouprefers to alkyl linked to a carbonyl group.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons,and more preferably 1 to 8 carbons in the normal chain, which includeone to six double bonds in the normal chain, and may optionally includean oxygen or nitrogen in the normal chain, such as vinyl, 2-propenyl,3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl,3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, andwhich may be optionally substituted with 1 to 4 substituents, namely,halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino,alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or anyof the substituents for alkyl set out herein.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbonsand more preferably 2 to 8 carbons in the normal chain, which includeone triple bond in the normal chain, and may optionally include anoxygen or nitrogen in the normal chain, such as 2-propynyl, 3-butynyl,2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl,4-dodecynyl and the like, and which may be optionally substituted with 1to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino,nitro, cyano, thiol, and/or alkylthio, and/or any of the substituentsfor alkyl set out herein.

The terms “arylalkenyl” and “arylalkynyl” as used alone or as part ofanother group refer to alkenyl and alkynyl groups as described abovehaving an aryl substituent.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

(CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³ , (CH₂)_(m), or(CH₂)_(n) includes alkylene, allenyl, alkenylene or alkynylene groups,as defined herein, each of which may optionally include an oxygen ornitrogen in the normal chain, which may optionally include 1, 2, or 3substituents which include alkyl, alkenyl, halogen, cyano, hydroxy,alkoxy, amino, thioalkyl, keto, C₃-C₆ cycloalkyl, alkylcarbonylamino oralkylcarbonyloxy; the alkyl substituent may be an alkylene moiety of 1to 4 carbons which may be attached to one or two carbons in the(CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³ or (CH₂)_(m) or(CH₂)_(n) group to form a cycloalkyl group therewith.

Examples of (CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³, (CH₂)_(m),(CH₂)_(n), alkylene, alkenylene and alkynylene include

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine as well as CF₃,with chlorine or fluorine being preferred.

The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

Unless otherwise indicated, the term “aryl” or the group

where Q is C, as employed herein alone or as part of another grouprefers to monocyclic and bicyclic aromatic groups containing 6 to 10carbons in the ring portion (such as phenyl or naphthyl including1-naphthyl and 2-naphthyl) and may optionally include one to threeadditional rings fused to a carbocyclic ring or a heterocyclic ring(such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings forexample

and may be optionally substituted through available carbon atoms with 1,2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl and/or any of the substituents for alkyl set outherein.

Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy”or “aralkoxy” as employed herein alone or as part of another groupincludes any of the above alkyl, aralkyl or aryl groups linked to anoxygen atom.

Unless otherwise indicated, the term “substituted amino” as employedherein alone or as part of another group refers to amino substitutedwith one or two substituents, which may be the same or different, suchas alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituentsmay be further substituted with a carboxylic acid and/or any of thesubstituents for alkyl as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl or hydroxy.

Unless otherwise indicated, the term “lower alkylthio”, alkylthio”,“arylthio” or “aralkylthio” as employed herein alone or as part ofanother group includes any of the above alkyl, aralkyl or aryl groupslinked to a sulfur atom.

Unless otherwise indicated, the term “lower alkylamino”, “alkylamino”,“arylamino”, or “arylalkylamino” as employed herein alone or as part ofanother group includes any of the above alkyl, aryl or arylalkyl groupslinked to a nitrogen atom.

Unless otherwise indicated, the term “acyl” as employed herein by itselfor part of another group, as defined herein, refers to an organicradical linked to a carbonyl

group; examples of acyl groups include any of the R³ groups attached toa carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl,cycloalkanoyl, cycloheteroalkanoyl and the like.

Unless otherwise indicated, the term “cycloheteroalkyl” as used hereinalone or as part of another group refers to a 5-, 6- or 7-memberedsaturated or partially unsaturated ring which includes 1 to 2 heteroatoms such as nitrogen, oxygen and/or sulfur, linked through a carbonatom or a heteroatom, where possible, optionally via the linker(CH₂)_(p) (where p is 1, 2 or 3), such as

and the like. The above groups may include 1 to 4 substituents such asalkyl, halo, oxo and/or any of of the substituents for alkyl or aryl setout herein. In addition, any of the cycloheteroalkyl rings can be fusedto a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

Unless otherwise indicated, the term “heteroaryl” as used herein aloneor as part of another group refers to a 5- or 6-membered aromatic ringincluding

where Q is N, which includes 1, 2, 3 or 4 hetero atoms such as nitrogen,oxygen or sulfur, and such rings fused to an aryl, cycloalkyl,heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), andincludes possible N-oxides. The heteroaryl group may optionally include1 to 4 substituents such as any of the the substituents for alkyl oraryl set out above. Examples of heteroaryl groups include the following:

and the like.

Examples of

groups include, but are not limited to:

Examples of

groups include, but are not limited to,

The term “cycloheteroalkylalkyl” as used herein alone or as part ofanother group refers to cycloheteroalkyl groups as defined above linkedthrough a C atom or heteroatom to a (CH₂)_(p) chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein aloneor as part of another group refers to a heteroaryl group as definedabove linked through a C atom or heteroatom to a —(CH₂)_(p)— chain,alkylene or alkenylene as defined above.

The term “polyhaloalkyl” as used herein refers to an “alkyl” group asdefined above which includes from 2 to 9, preferably from 2 to 5, halosubstituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃ orCF₃CF₂CH₂.

The term “polyhaloalkyloxy” as used herein refers to an “alkoxy” or“alkyloxy” group as defined above which includes from 2 to 9, preferablyfrom 2 to 5, halo substituents, such as F or Cl, preferably F, such asCF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

The term “prodrug esters” as employed herein includes prodrug esterswhich are known in the art for carboxylic and phosphorus acid esterssuch as methyl, ethyl, benzyl and the like. Other prodrug ester examplesof R⁴ include the following groups: (1-alkanoyloxy)alkyl such as,

wherein R^(a), R^(b) and R^(c) are H, alkyl, aryl or arylalkyl; however,R^(a)O cannot be HO.

Examples of such prodrug esters R⁴ include

Other examples of suitable prodrug esters R⁴ include

wherein R^(a) can be H, alkyl (such as methyl or t-butyl), arylalkyl(such as benzyl) or aryl (such as phenyl); R^(d) is H, alkyl, halogen oralkoxy, R^(e) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is 0, 1 or 2.

Where the compounds of structure I are in acid form they may form apharmaceutically acceptable salt such as alkali metal salts such aslithium, sodium or potassium, alkaline earth metal salts such as calciumor magnesium as well as zinc or aluminum and other cations such asammonium, choline, diethanolamine, lysine (D or L), ethylenediamine,t-butylamine, t-octylamine, tris-(hydroxymethyl)aminomethane (TRIS),N-methyl glucosamine (NMG), triethanolamine and dehydroabietylamine.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

Where desired, the compounds of structure I may be used in combinationwith one or more hypolipidemic agents or lipid-lowering agents or lipidmodulating agents and/or one or more other types of therapeutic agentsincluding antidiabetic agents, anti-obesity agents, antihypertensiveagents, platelet aggregation inhibitors, and/or anti-osteoporosisagents, which may be administered orally in the same dosage form, in aseparate oral dosage form or by injection.

The hypolipidemic agent or lipid-lowering agent or lipid modulatingagents which may be optionally employed in combination with thecompounds of formula I of the invention may include 1,2,3 or more MTPinhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, and/or nicotinic acid and derivatives thereof.

MTP inhibitors employed herein include MTP inhibitors disclosed in U.S.Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279,U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No.5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20, 1998,now U.S. Pat. No. 5,962,440. Preferred are each of the preferred MTPinhibitors disclosed in each of the above patents and applications.

All of the above U.S. patents and applications are incorporated hereinby reference.

Most preferred MTP inhibitors to be employed in accordance with thepresent invention include preferred MTP inhibitors as set out in U.S.Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

The hypolipidemic agent may be an HMG CoA reductase inhibitor whichincludes, but is not limited to, mevastatin and related compounds asdisclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and relatedcompounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin andrelated compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, itavastatin(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in U.S.Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat.No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No.0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use herein are disclosed in GB 2205837.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol.31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp16, 17, 40-43, 48-51, Summary.

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836,probucol and gemfibrozil being preferred, bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®)and cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil(HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine(SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814(azulene derivative), melinamide (Sumitomo), Sandoz 58-035, AmericanCyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives),nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylicacid, aspirin, poly(diallylmethylamine) derivatives such as disclosed inU.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The hypolipidemic agent may be an ACAT inhibitor such as disclosed in,Drugs of the Future 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor,Cl-1011 is effective in the prevention and regression of aortic fattystreak area in hamsters”, Nicolosi et al, Atherosclerosis (Shannon,Irel). (1998), 137(1), 77-85; “The pharmacological profile of FCE 27677:a novel ACAT inhibitor with potent hypolipidemic activity mediated byselective suppression of the hepatic secretion of ApoB100-containinglipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1),16-30; “RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACATinhibitor”, Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1),47-50; “ACAT inhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem.(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd).

The hypolipidemic agent may be an upregulator of LD2 receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 as well as those disclosed inAtherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipid-modulating agent may be a cholesteryl ester transfer protein(CETP) inhibitor such as Pfizer's CP 529,414 (WO/0038722 and EP 818448)and Pharmacia's SC-744 and SC-795.

The ATP citrate lyase inhibitor which may be employed in the combinationof the invention may include, for example, those disclosed in U.S. Pat.No. 5,447,954.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, itavastatin and visastatin andZD-4522.

The above-mentioned U.S. patents are incorporated herein by reference.The amounts and dosages employed will be as indicated in the Physician'sDesk Reference and/or in the patents set out above.

The compounds of formula I of the invention will be employed in a weightratio to the hypolipidemic agent (were present), within the range fromabout 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

The dosages and formulations for the hypolipidemic agent will be asdisclosed in the various patents and applications discussed above.

The dosages and formulations for the other hypolipidemic agent to beemployed, where applicable, will be as set out in the latest edition ofthe Physicians' Desk Reference.

For oral administration, a satisfactory result may be obtained employingthe MTP inhibitor in an amount within the range of from about 0.01 mg toabout 500 mg and preferably from about 0.1 mg to about 100 mg, one tofour times daily.

A preferred oral dosage form, such as tablets or capsules, will containthe MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

For oral administration, a satisfactory result may be obtained employingan HMG CoA reductase inhibitor, for example, pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin or cerivastatin in dosagesemployed as indicated in the Physician's Desk Reference, such as in anamount within the range of from about 1 to 2000 mg, and preferably fromabout 4 to about 200 mg.

The squalene synthetase inhibitor may be employed in dosages in anamount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will containthe HMG CoA reductase inhibitor in an amount from about 0.1 to about 100mg, preferably from about 0.5 to about 80 mg, and more preferably fromabout 1 to about 40 mg.

A preferred oral dosage form, such as tablets or capsules will containthe squalene synthetase inhibitor in an amount of from about 10 to about500 mg, preferably from about 25 to about 200 mg.

The hypolipidemic agent may also be a lipoxygenase inhibitor including a15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives asdisclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613,isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors asdisclosed by Sendobry et al “Attenuation of diet-induced atherosclerosisin rabbits with a highly selective 15-lipoxygenase inhibitor lackingsignificant antioxidant properties”, Brit. J. Pharmacology (1997) 120,1199-1206, and Cornicelli et al, “15-Lipoxygenase and its Inhibition: ANovel Therapeutic Target for Vascular Disease”, Current PharmaceuticalDesign, 1999, 5, 11-20.

The compounds of formula I and the hypolipidemic agent may be employedtogether in the same oral dosage form or in separate oral dosage formstaken at the same time.

The compositions described above may be administered in the dosage formsas described above in single or divided doses of one to four timesdaily. It may be advisable to start a patient on a low dose combinationand work up gradually to a high dose combination.

The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or cerivastatin as well as niacinand/or cholestagel.

The other antidiabetic agent which may be optionally employed incombination with the compound of formula I may be 1,2,3 or moreantidiabetic agents or antihyperglycemic agents including insulinsecretagogues or insulin sensitizers, or other antidiabetic agentspreferably having a mechanism of action different from the compounds offormula I of the invention, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPAR γ agonists, such asthiazolidinediones, aP2 inhibitors, dipeptidyl peptidase IV (DP4)inhibitors, SGLT2 inhibitors, and/or meglitinides, as well as insulin,and/or glucagon-like peptide-1 (GLP-1).

The other antidiabetic agent may be an oral antihyperglycemic agentpreferably a biguanide such as metformin or phenformin or salts thereof,preferably metformin HCl.

Where the antidiabetic agent is a biguanide, the compounds of structureI will be employed in a weight ratio to biguanide within the range fromabout 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.

The other antidiabetic agent may also preferably be a sulfonyl urea suchas glyburide (also known as glibenclamide), glimepiride (disclosed inU.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the β-cells, with glyburide and glipizide beingpreferred, which may be administered in the same or in separate oraldosage forms.

The compounds of structure I will be employed in a weight ratio to thesulfonyl urea in the range from about 0.01:1 to about 100:1, preferablyfrom about 0.02:1 to about 5:1.

The oral antidiabetic agent may also be a glucosidase inhibitor such asacarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosedin U.S. Pat. No. 4,639,436), which may be administered in the same or ina separate oral dosage forms.

The compounds of structure I will be employed in a weight ratio to theglucosidase inhibitor within the range from about 0.01:1 to about 100:1,preferably from about 0.05:1 to about 10:1.

The compounds of structure I may be employed in combination with a PPARγ agonist such as a thiazolidinedione oral anti-diabetic agent or otherinsulin sensitizers (which has an insulin sensitivity effect in NIDDMpatients) such as troglitazone (Warner-Lambert's Rezulin®, disclosed inU.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda),Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

The compounds of structure I will be employed in a weight ratio to thethiazolidinedione in an amount within the range from about 0.01:1 toabout 100:1, preferably from about 0.05 to about 10:1.

The sulfonyl urea and thiazolidinedione in amounts of less than about150 mg oral antidiabetic agent may be incorporated in a single tabletwith the compounds of structure I.

The compounds of structure I may also be employed in combination with aantihyperglycemic agent such as insulin or with glucagon-like peptide-1(GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (asdisclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of whichis incorporated herein by reference), as well as AC2993 (Amylin) andLY-315902 (Lilly), which may be administered via injection, intranasal,inhalation or by transdermal or buccal devices.

Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physician's DeskReference (PDR).

Where present, metformin or salt thereof may be employed in amountswithin the range from about 500 to about 2000 mg per day which may beadministered in single or divided doses one to four times daily.

Where present, the thiazolidinedione anti-diabetic agent may be employedin amounts within the range from about 0.01 to about 2000 mg/day whichmay be administered in single or divided doses one to four times perday.

Where present insulin may be employed in formulations, amounts anddosing as indicated by the Physician's Desk Reference.

Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which areincorporated herein by reference.

The other antidiabetic agent may also be a PPAR α/γ dual agonist such asAR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (KyorinMerck) as well as those disclosed by Murakami et al, “A Novel InsulinSensitizer Acts As a Coligand for Peroxisome Proliferation-ActivatedReceptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alphaActivation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats”,Diabetes 47, 1841-1847 (1998).

The antidiabetic agent may be an SGLT2 inhibitor such as disclosed inU.S. application Ser. No. 09/679,027, filed Oct. 4, 2000 (attorney fileLA49 NP), employing dosages as set out therein. Preferred are thecompounds designated as preferred in the above application.

The antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S.application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S.application Ser. No. 09/519,079, filed Mar. 6, 2000 (attorney file LA27NP), employing dosages as set out herein. Preferred are the compoundsdesignated as preferred in the above application.

The antidiabetic agent may be a DP4 inhibitor such as disclosed in U.S.application Ser. No. 09/788,173 filed Feb. 16, 2001 (attorney fileLA50), WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278(PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al, Biochemistry,38(36), 11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

The meglitinide which may optionally be employed in combination with thecompound of formula I of the invention may be repaglinide, nateglinide(Novartis) or KAD1229 (PF/Kissei), with repaglinide being preferred.

The compound of formula I will be employed in a weight ratio to themeglitinide, PPAR γ agonist, PPAR α/γ dual agonist, aP2 inhibitor, DP4inhibitor or SGLT2 inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.05 to about 10:1.

The other type of therapeutic agent which may be optionally employedwith a compound of formula I may be 1, 2, 3 or more of an anti-obesityagent including a beta 3 adrenergic agonist, a lipase inhibitor, aserotonin (and dopamine) reuptake inhibitor, an aP2 inhibitor, a thyroidreceptor agonist and/or an anorectic agent.

The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula I may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648being preferred.

The lipase inhibitor which may be optionally employed in combinationwith a compound of formula I may be orlistat or ATL-962 (Alizyme), withorlistat being preferred.

The serotonin (and dopoamine) reuptake inhibitor which may be optionallyemployed in combination with a compound of formula I may be sibutramine,topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramineand topiramate being preferred.

The thyroid receptor agonist which may be optionally employed incombination with a compound of formula I may be a thyroid receptorligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio),GB98/284425 (KaroBio), and U.S. Provisional Application 60/183,223 filedFeb. 17, 2000, with compounds of the KaroBio applications and the aboveU.S. provisional application being preferred.

The anorectic agent which may be optionally employed in combination witha compound of formula I may be dexamphetamine, phentermine,phenylpropanolamine or mazindol, with dexamphetamine being preferred.

The various anti-obesity agents described above may be employed in thesame dosage form with the compound of formula I or in different dosageforms, in dosages and regimens as generally known in the art or in thePDR.

The antihypertensive agents which may be employed in combination withthe compound of formula I of the invention include ACE inhibitors,angiotensin II receptor antagonists, NEP/ACE inhibitors, as well ascalcium channel blockers, β-adrenergic blockers and other types ofantihypertensive agents including diuretics.

The angiotensin converting enzyme inhibitor which may be employed hereinincludes those containing a mercapto (—S—) moiety such as substitutedproline derivatives, such as any of those disclosed in U.S. Pat. No.4,046,889 to Ondetti et al mentioned above, with captopril, that is,1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, andmercaptoacyl derivatives of substituted prolines such as any of thosedisclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred.

Other examples of mercapto containing ACE inhibitors that may beemployed herein include rentiapril (fentiapril, Santen) disclosed inClin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril andYS980.

Other examples of angiotensin converting enzyme inhibitors which may beemployed herein include any of those disclosed in U.S. Pat. No.4,374,829 mentioned above, withN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,enalapril, being preferred, any of the phosphonate substituted amino orimino acids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolineor (ceronapril) being preferred, phosphinylalkanoyl prolines disclosedin U.S. Pat. No. 4,168,267 mentioned above with fosinopril beingpreferred, any of the phosphinylalkanoyl substituted prolines disclosedin U.S. Pat. No. 4,337,201, and the phosphonamidates disclosed in U.S.Pat. No. 4,432,971 discussed above.

Other examples of ACE inhibitors that may be employed herein includeBeecham's BRL 36,378 as disclosed in European Patent Application Nos.80822 and 60668; Chugai's MC-838 disclosed in C.A. 102:72588v and Jap.J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986);ramipril (Hoechsst) disclosed in Euro. Patent No. 79-022 and Curr. Ther.Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung34:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc.Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in FEBSLett. 165:201 (1984); lisinopril (Merck), indalapril (delapril)disclosed in U.S. Pat. No. 4,385,051; indolapril (Schering) disclosed inJ. Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering)disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986);perindopril (Servier) disclosed in Eur. J. clin. Pharmacol. 31:519(1987); quinapril (Warner-Lambert) disclosed in U.S. Pat. No. 4,344,949and CI925 (Warner-Lambert)([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid HCl)disclosed in Pharmacologist 26:243, 266 (1984), WY-44221(Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

Preferred ACE inhibitors are captopril, fosinopril, enalapril,lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

NEP/ACE inhibitors may also be employed herein in that they possessneutral endopeptidase (NEP) inhibitory activity and angiotensinconverting enzyme (ACE) inhibitory activity. Examples of NEP/ACEinhibitors suitable for use herein include those disclosed in U.S. Pat.Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688,U.S. Pat. No. 5,552,397, U.S. Pat. No. 5,504,080, U.S. Pat. No.5,612,359,U.S. Pat. No. 5,525,723, European Patent Application 0599,444,0481,522, 0599,444, 0595,610, European Patent Application 0534363A2,534,396 and 534,492, and European Patent Application 0629627A2.

Preferred are those NEP/ACE inhibitors and dosages thereof which aredesignated as preferred in the above patents/applications which U.S.patents are incorporated herein by reference; most preferred areomapatrilat, BMS 189,921([S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat)) and CGS 30440.

The angiotensin II receptor antagonist (also referred to herein asangiotensin II antagonist or AII antagonist) suitable for use hereinincludes, but is not limited to, irbesartan, losartan, valsartan,candesartan, telmisartan, tasosartan or eprosartan, with irbesartan,losartan or valsartan being preferred.

A preferred oral dosage form, such as tablets or capsules, will containthe ACE inhibitor or AII antagonist in an amount within the range fromabut 0.1 to about 500 mg, preferably from about 5 to about 200 mg andmore preferably from about 10 to about 150 mg.

For parenteral administration, the ACE inhibitor, angiotensin IIantagonist or NEP/ACE inhibitor will be employed in an amount within therange from about 0.005 mg/kg to about 10 mg/kg and preferably from about0.01 mg/kg to about 1 mg/kg.

Where a drug is to be administered intravenously, it will be formulatedin conventional vehicles, such as distilled water, saline, Ringer'ssolution or other conventional carriers.

It will be appreciated that preferred dosages of ACE inhibitor and AIIantagonist as well as other antihypertensives disclosed herein will beas set out in the latest edition of the Physician's Desk Reference(PDR).

Other examples of preferred antihypertensive agents suitable for useherein include omapatrilat (Vanlev®) amlodipine besylate (Norvasc®),prazosin HCl (Minipress®), verapamil, nifedipine, nadolol, diltiazem,felodipine, nisoldipine, isradipine, nicardipine, atenolol, carvedilol,sotalol, terazosin, doxazosin, propranolol, and clonidine HCl(Catapres®).

Diuretics which may be employed in combination with compounds of formulaI include hydrochlorothiazide, torasemide, furosemide, spironolactono,and indapamide.

Antiplatelet agents which may be employed in combination with compoundsof formula I of the invention include aspirin, clopidogrel, ticlopidine,dipyridamole, abciximab, tirofiban, eptifibatide, anagrelide, andifetroban, with clopidogrel and aspirin being preferred.

The antiplatelet drugs may be employed in amounts as indicated in thePDR. Ifetroban may be employed in amounts as set out in U.S. Pat. No.5,100,889.

Antiosteoporosis agents suitable for use herein in combination with thecompounds of formula I of the invention include parathyroid hormone orbisphosphonates, such as MK-217 (alendronate) (Fosamax®). Dosagesemployed will be as set out in the Physician's Desk Reference.

In carrying our the method of the invention, a pharmaceuticalcomposition will be employed containing the compounds of structure I,with or without another therapeutic agent, in association with apharmaceutical vehicle or diluent. The pharmaceutical composition can beformulated employing conventional solid or liquid vehicles or diluentsand pharmaceutical additives of a type appropriate to the mode ofdesired administration. The compounds can be administered to mammalianspecies including humans, monkeys, dogs, etc. by an oral route, forexample, in the form of tablets, capsules, granules or powders, or theycan be administered by a parenteral route in the form of injectablepreparations. The dose for adults is preferably between 50 and 2,000 mgper day, which can be administered in a single dose or in the form ofindividual doses from 1-4 times per day.

A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

The following Examples represent preferred embodiments of the invention.

The following abbreviations are employed in the Examples:

-   Ph=phenyl-   Bn=benzyl-   t-Bu=tertiary butyl-   Me=methyl-   Et=ethyl-   TMS=trimethylsilyl-   TMSN₃=trimethylsilyl azide-   TBS=tert-butyldimethylsilyl-   FMOC=fluorenylmethoxycarbonyl-   Boc=tert-butoxycarbonyl-   Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   THF=tetrahydrofuran-   Et₂O=diethyl ether-   hex=hexanes-   EtOAc=ethyl acetate-   DMF=dimethyl formamide-   MeOH=methanol-   EtOH=ethanol-   i-PrOH=isopropanol-   DMSO=dimethyl sulfoxide-   DME=1,2 dimethoxyethane-   DCE=1,2 dichloroethane-   HMPA=hexamethyl phosphoric triamide-   HOAc or AcOH=acetic acid-   TFA=trifluoroacetic acid-   TFAA=trifluoroacetic anhydride-   i-Pr₂NEt=diisopropylethylamine-   Et₃N=triethylamine-   NMM=N-methyl morpholine-   DMAP=4-dimethylaminopyridine-   NaBH₄=sodium borohydride-   NaBH(OAc)₃=sodium triacetoxyborohydride-   DIBALH=diisobutyl aluminum hydride-   LiAlH₄=lithium aluminum hydride-   n-BuLi=n-butyllithium-   Pd/C=palladium on carbon-   PtO₂=platinum oxide-   KOH=potassium hydroxide-   NaOH=sodium hydroxide-   LiOH=lithium hydroxide-   K₂CO₃=potassium carbonate-   NaHCO₃=sodium bicarbonate-   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene-   EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or    EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or    1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)-   HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate-   HOAT=1-Hydroxy-7-azabenzotriazole-   BOP reagent=benzotriazol-1-yloxy-tris (dimethylamino) phosphonium    hexafluorophosphate-   NaN(TMS)₂=sodium hexamethyldisilazide or sodium    bis(trimethylsilyl)amide-   Ph₃P=triphenylphosphine-   Pd(OAc)₂=Palladium acetate-   (Ph₃P)₄Pd^(o)=tetrakis triphenylphosphine palladium-   DEAD=diethyl azodicarboxylate-   DIAD=diisopropyl azodicarboxylate-   Cbz-Cl=benzyl chloroformate-   CAN=ceric ammonium nitrate-   SAX=Strong Anion Exchanger-   SCX=Strong Cation Exchanger-   Ar=argon-   N₂=nitrogen-   min=minute(s)-   h or hr=hour(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   meq=milliequivalent-   RT=room temperature-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   HPLC=high performance liquid chromatography-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   NMR=nuclear magnetic resonance-   NMR spectral data: s=singlet; d=doublet; m=multiplet; br=broad;    t=triplet-   mp=melting point

EXAMPLE 1

To a 0° C. solution of Meldrum's acid (9.4 g; 65 mmol) and pyridine (8.0g; 100 mmol) in CH₂Cl₂ was added dropwise 3-methoxyphenylacetyl chloride(10.0 g; 54 mmol) over 2 h. The resultant mixture was stirred at RT for2 h, then partitioned between aq. 2N HCl and CH₂Cl₂. The organic layerwas dried (Na₂SO₄) and concentrated in vacuo to give crude Part Acompound as an oil. This material was used in the next step withoutfurther purification.

A solution of the crude Part A compound and aniline (5.0 g; 54 mmol) intoluene (20 mL) was heated to reflux for 3 h. The reaction solution wasthen washed with aq 1M HCl, then concentrated in vacuo to a smallvolume, upon which the desired product Part B compound (9.0 g; 59%)precipitated as a yellow solid.

To 0° C. aqueous H₂SO₄ (5 mL of a 1.84 M solution) was added dropwiseover 20 min a solution of Part B compound (6.0 g; 14 mmol), NaNO₂ (1.38g; 20 mmol) and aq. 1 M NaOH (14 mL). The reaction mixture was stirredat 0° C. for 30 min; the resulting precipitate was filtered off andwashed with H₂O to provide a yellow solid. This material waschromatographed (SiO₂; stepwise gradient from 5:1 to 3:1 hex:EtOAc) togive Part C compound (3.0 mg; 68%) as yellow crystals.

A solution of Part C compound (0.100 g; 0.32 mmol), phenylhydrazine(0.060 g; 0.55 mmol) and MgSO₄ (200 mg) was refluxed in EtOH (10 mL) for2 h, at which point starting material had been consumed by analyticalHPLC. Volatiles were removed in vacuo and the residue was recrystallizedfrom hexane/CH₂Cl₂ (1:1) to provide Part D compound (90 mg; 70%) asyellow crystals.

A mixture of Part D compound (90 mg; 0.22 mmol), TFAA (1 mL) and TFA (1mL) was heated in a sealed tube at 45° C. for 10 h. At this pointstarting material had been consumed by analytical HPLC. Volatiles wereremoved in vacuo and the residue was partitioned between EtOAc and aqNaHCO₃. The organic phase was dried (Na₂SO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; 3:1 hex:EtOAc) to give Part Ecompound (30 mg; 35%) as a yellow solid.

To a −70° C. solution of Part E compound (30 mg; 0.078 mmol) in CH₂Cl₂(2.0 mL) was added dropwise BBr₃ (1.0 mL of a 1M solution in CH₂Cl₂).The mixture was allowed to warm to 0° C. and stirred at 0° C. for 3 h.The reaction was cooled to −20° C. and quenched with aq. NH₄Cl solution.This mixture was allowed to warm to RT and stirred for 30 min, thenextracted with EtOAc. The organic phase was washed successively with aq1 M HCl and water, then dried (Na₂SO₄) and concentrated in vacuo to givecrude Part F compound (30 mg; 99%) as an oil which was used in the nextstep without further purification.

A mixture of Part F compound (30 mg; 0.081 mmol), 5-methyl 2-phenyloxazole 4-ethanol mesylate (30 mg; 0.11 mmol; prepared as described inExample 11) and K₂CO₃ (500 mg; 3.61 mmol) in DMF (3 mL) was stirred at80° C. for 12 h. LC/MS indicated that starting material had beencompletely consumed. The reaction mixture was filtered and the filtratewas concentrated in vacuo to give an oil, which was chromatographed(SiO₂; 3:1 hex:EtOAc) to give Part G compound (12 mg; 36%) as a lightbrown solid.

A solution of Part G compound (38 mg; 0.054 mmol) and KOH (200 mg; 3.6mmol) in EtOH (30 mL) in a sealed tube was heated at 90° C. for 24 h.The reaction mixture was partitioned between EtOAc and aq 1 M HCl. Theorganic phase was washed with water, dried (Na₂SO₄) and concentrated invacuo. The resulting oil was purified by preparative HPLC (YMC reversephase column; continuous gradient from 30:70 B:A to 100% B) to give thetitle compound (8 mgs; 31%) as a solid. [M+H]⁺=481.1

¹H NMR (CDCl₃; 400 MHz) δ: 2.43 (s, 3H), 3.05 (t, 2H; J=Hz), 4.26 (t,2H; J=Hz), 4.35 (s, 2H), 6.73 (dd, 1H; J=Hz), 6.93 (d, 1H; J=Hz), 7.14(dd, 2H; J=Hz), 7.41 (t, 1H; J=Hz), 7.47-7.54 (m, 5H), 8.05 (dd, 2H;J=Hz), 8.10 (dd, 2H; J=Hz), 11.32 (br s, 1H). ¹³C NMR (CDCl₃; 100 MHz)δ: 10.2, 24.5, 31.7, 65.6, 113.6, 114.7, 119.4, 121.6, 124.5, 126.7,128.4, 129.2, 129.3, 129.5, 130.1, 131.9, 137.5, 139.1, 139.6, 146.8,151.4, 157.9, 160.2, 163.5

EXAMPLE 1 Alternative Synthesis

A solution of 3-hydroxyphenylacetic acid (3.89 g; 25 mmol) andconcentrated H₂SO₄ (4 drops) in MeOH (30 mL) was heated at refluxovernight, then cooled to RT and concentrated in vacuo. The residue waspartitioned between EtOAc (150 mL) and saturated aqueous NaHCO₃ (20 mL).The organic phase was dried (MgSO₄) and concentrated in vacuo to providePart A compound (3.80 g; 92%) as an oil.

A mixture of Part A compound (5.50 g; 33 mmol), 5-methyl 2-phenyloxazole 4-ethanol mesylate (5.43 g; 19 mmol; prepared as described inExample 11) and K₂CO₃ (5.50 g; 40 mmol) in MeCN (50 mL) was heated atreflux overnight, then cooled to RT and filtered. The filtrate wasconcentrated in vacuo, then partitioned between EtOAc (150 mL) and 1 Naqueous NaOH (15 mL). The organic phase was washed with 1 N aqueous NaOH(15 mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from hexane to 7:3hexane:EtOAc over 10 min; then at 7:3 hex:EtOAc for 15 min, thencontinuous gradient from 7:3 to 2:3 hex:EtOAc for 5 min, then at 2:3hex:EtOAc for 15 min) to provide Part B compound (4.30 g; 64%) as aviscous oil.

A mixture of Part B compound (4.30 g; 12 mmol) and LiOH.H₂O (1.02 g; 24mmol) in 1:1 THF:H₂O (60 mL) was stirred overnight at RT, after whichaqueous HCl (15 mL of a 1 N solution) was added. Organic solvents wereremoved in vacuo and the aqueous phase was extracted with EtOAc (2×120mL). The combined organic extracts were dried (Na₂SO₄) and concentratedin vacuo. The residue was stripped from toluene (50 mL) to give Part Ccompound (4.12 g; 100%) which was used in the next step without furtherpurification.

To a solution of Part C compound (4.12 g; 12 mmol) in anhydrous CH₂Cl₂was added dropwise a solution of oxalyl chloride in CH₂Cl₂ (15.3 mL of a2 M solution; 15 mmol). The mixture was stirred at RT for 2 h, thenconcentrated in vacuo. The residue was stripped from toluene (50 mL) toprovide Part D as a yellow solid, which was used in the next stepwithout further purification.

To a 0° C. solution of Meldrum's acid (2.16 g; 15 mmol) in anhydrousCH₂Cl₂ (44 mL) was added pyridine (3.63 mL; 45 mmol) dropwise over 15min. A solution of Part D compound in anhydrous CH₂Cl₂ (44 mL) was thenadded dropwise by syringe pump over 2 h. The reaction was warmed to RTand stirred at RT overnight, after which it was partitioned betweenEtOAc (300 mL) and aqueous HCl (30 mL of a 1 N solution). The organicphase was dried (MgSO₄) and concentrated in vacuo to give Part Ecompound.

A solution of the crude Part E compound and aniline (1.1 mL; 12 mmol) intoluene (22 mL) was heated to reflux for 2 h. The reaction solution waspartitioned between EtOAc (150 mL) and aqueous 1M HCl (20 mL); theorganic phase was concentrated in vacuo. The residue was chromatographed(SiO₂; stepwise gradient from 100% hexane to 2:3 hex:EtOAc to 2:5hex:EtOAc) to give Part F compound (4.27 g; 77% overall for 3 steps)precipitated as a yellow solid.

A solution of Part F compound (4.27 g; 9.40 mmol), p-toluenesulfonylazide (2.50 mg; 12.7 mmol) and Et₃N (1.83 mL; 13.1 mmol) in CH₂Cl₂ (60mL) was stirred at RT for 2.5 h. Volatiles were removed in vacuo, andthe residue was chromatographed (SiO₂; stepwise gradient from 1:1hex:EtOAc to 100% EtOAc to 10:1 EtOAc:MeOH) to provide Part G compound(3.50 g; 77%) as a yellow solid.

A mixture of Part G compound (3.50 mg; 7.24 mmol), benzylamine (1.13 mL;11.1 mmol) and TiCl₄ (7.24 mL of a 1 M solution in CH₂Cl₂; 7.24 mmol) inDCE (100 mL) was heated at 88° C. in a sealed tube for 2 h. The reactionmixture was cooled to RT and partitioned between EtOAc (200 mL) and H₂O(50 mL). The organic phase was dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 100%hexane to 1:1 hex:EtOAc) to give Part H compound (2.30 g; 55%) as alight-brown solid foam.

A mixture of Part H compound (2.0 g; 3.51 mmol) and KOH (4.35 g; 77mmol) was heated in EtOH (75 mL) at 118° C. for 3 h. At this point,HPLC/MS showed that reaction was complete. The reaction mixture wascooled to RT and partitioned between EtOAc (150 mL), H₂O (20 mL) andexcess concentrated HCl (6 mL). The organic phase was washed with H₂O,dried (MgSO₄) and concentrated in vacuo to give the crude acid as abrown solid. This material was dissolved in a solution of saturated HClin MeOH (30 mL) and the reaction was stirred at RT for 4 days, thenconcentrated in vacuo. The residue was partitioned between EtOAc (150mL) and saturated aqueous NaHCO₃ (20 mL). The organic phase wasconcentrated in vacuo and the residue was chromatographed (SiO2;continuous gradient from 100% hexane to 1:1 hex:EtOAc over 20 min, then1:1 hex:EtOAc for 20 min) to give Part I compound (1.35 g; 76%) as asolid.

A mixture of Part I compound (1.35 g; 2.65 mmol) and 10% palladium oncarbon (1.35 g) in MeOH (60 mL) and a solution of saturated HCl in MeOH(1 mL) was stirred under an atmosphere of H₂ (balloon) for 70 h. Theballoon was removed, additional MeOH (60 mL) was added and the mixturewas heated to reflux and filtered hot. The filtrate was concentrated invacuo to give Part J compound (1.10 g; 91%) as a white solid.

To a mixture of Part J compound (25 mg; 0.55 mmol), phenyl boronic acid(22 mg; 1.80 mmol) and Cu(OAc)₂ (16 mg; 0.88 mmol) were added pyridine(50 μL) and Et₃N (50 μL). The mixture was stirred at RT overnight, thenwas partitioned between EtOAc and H₂O (10 mL each). The organic phasewas concentrated in vacuo, and the residue was chromatographed (SiO₂;stepwise gradient from 5:1 to 3:1 hexane:EtOAc) to give Part K compound(3 mg; 10%) as an oil.

A mixture of Part K compound (3 mg; 0.006 mmol) and LiOH.H₂O (2 mg; 0.48mmol) in 1:1 THF:H₂O (0.60 mL) was stirred for 4 h at RT, then the THFwas removed in vacuo. Aqueous 1 N HCl was added until the pH was ˜3, andthe mixture was extracted with EtOAc (5 mL). The organic phase wasconcentrated in vacuo, and the residue was purified by preparative HPLC(YMC reverse-phase ODS 20×100 mm column; flow rate=20 mL/min; 10 mincontinuous gradient from 25:75 B:A to 100% B+5 min hold-time at 100% B,where solvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (1.2 mg; 41%) as a colorlessoil.

[M+H]⁺=481

EXAMPLE 2

The method described in Example 1 was used except that4-methylphenylhydrazine was used instead of phenylhydrazine to preparethe title compound.

[M+H]⁺=495.0

EXAMPLE 3

To a 0° C. solution of Meldrum's acid (9.4 g; 65 mmol) and pyridine (8.0g; 100 mmol) in CH₂Cl₂ was added dropwise 4-methoxyphenylacetyl chloride(10.0 g; 54 mmol) over 2 h. The resultant mixture was stirred at RT for2 h, then partitioned between aq. 2N HCl and CH₂Cl₂. The organic layerwas dried (Na₂SO₄) and concentrated in vacuo to give crude Part Acompound as an oil. This material was used in the next step withoutfurther purification.

A solution of the crude Part A compound and aniline (5.0 g; 54 mmol) intoluene (20 mL) was heated to reflux for 3 h. The reaction solution wasthen washed with aq 1M HCl, then concentrated in vacuo to a smallvolume, upon which the desired product Part B compound (7.5 g; 49%)precipitated as a yellow solid.

To 0° C. aqueous H₂SO₄ (5 mL of a 1.84 M solution) was added dropwiseover 20 min a solution of Part B compound (2.0 g; 7.1 mmol), NaNO₂ (0.73g; 10.6 mmol), aq. 1 M NaOH (7.06 mL) and THF (50 mL). The reactionmixture was stirred at 0° C. for 30 min; the resulting precipitate wasfiltered off and washed with H₂O to provid a yellow solid. This materialwas chromatographed (SiO₂; stepwise gradient from 5:1 to 3:1 hex:EtOAc)to give Part C compound (2.00 g; 91%) as yellow crystals.

A solution of Part C compound (0.250 g; 0.80 mmol), phenylhydrazine(0.097 g; 0.90 mmol) and MgSO₄ (2 g) was refluxed in EtOH (10 mL) for 2h, at which point starting material had been consumed by analyticalHPLC. Volatiles were removed in vacuo and the residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 1:1 hex:EtOAc) toprovide Part D compound (200 mg; 62%) as a yellow solid.

A mixture of Part D compound (30 mg; 0.075 mmol), TFAA (1 mL) and TFA (1mL) was heated in a sealed tube at 45° C. for 10 h. At this pointstarting material had been consumed by analytical HPLC. Volatiles wereremoved in vacuo and the residue was partitioned between EtOAc and aqNaHCO₃. The organic phase was dried (Na₂SO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; 3:1 hex:EtOAc) to give Part Ecompound (25 mg; 86%) as a yellow solid.

To a −70° C. solution of Part E compound (25 mg; 0.065 mmol) in CH₂Cl₂(2.0 mL) was added dropwise BBr₃ (1.0 mL of a 1 M solution in CH₂Cl₂).The mixture was allowed to warm to 0° C. and stirred at 0° C. for 3 h.The reaction was cooled to −20° C. and quenched with aq. NH₄Cl solution.This mixture was allowed to warm to RT and stirred for 30 min, thenextracted with EtOAc. The organic phase was washed successively with aq1 M HCl and water, then dried (Na₂SO₄) and concentrated in vacuo to givecrude Part F compound (30 mg) as an oil which was used in the next stepwithout further purification.

A mixture of Part F compound (30 mg; 0.081 mmol), 5-methyl 2-phenyloxazole 4-ethanol mesylate (30 mg; 0.11 mmol; prepared as described inExample 11) and K₂CO₃ (500 mg; 3.61 mmol) in DMF (3 mL) was stirred at80° C. for 12 h. LC/MS indicated that starting material had beencompletely consumed. The reaction mixture was filtered and the filtratewas concentrated in vacuo to give an oil, which was chromatographed(SiO₂; 3:1 hex:EtOAc) to give Part G compound (13 mg; 28% over 2 steps)as a solid.

A solution of Part G compound (0.013 g; 0.023 mmol) and KOH (200 mg; 3.6mmol) in EtOH (30 mL) in a sealed tube was heated at 90° C. for 24 h.The reaction mixture was partitioned between EtOAc and aq 1 M HCl. Theorganic phase was washed with water, dried (Na₂SO₄) and concentrated invacuo. The resulting oil was purified by preparative HPLC (as describedfor the purification of BMS-460913; see below) to give the titlecompound (9 mg; 81%) as a solid. [M+H]⁺=481.1

EXAMPLE 4

The procedure of Example 3 was employed to prepare the title compoundexcept that 4-methylphenylhydrazine was used in place ofphenylhydrazine. [M+H]⁺=495.1.

EXAMPLE 5

To a 0° C. solution of methyl 4-hydroxyphenylacetate (2.66 g; 1.6 mmol),5-phenyl 2-methyl oxazole-3-ethanol (3.25 g; 1.6 mmol) and Ph₃P (5.0 g;1.9 mmol) in anhydrous THF (30 mL) was added DEAD (3.5 g; 2.0 mmol)dropwise. The reaction mixture was stirred at 0° C. for 30 min and thenwas allowed to warm to RT and stirred at RT overnight. Volatiles wereremoved in vacuo and the residue was chromatographed (SiO₂; stepwisegradient; hexane:EtOAc 5:1 to 5:2) to give Part A compound (3.5 g; 62%)as a white solid.

A solution of Part A compound (2.85 g; 0.812 mmol) and aqueous LiOH (2.0mL of a 1 M solution; 2.0 mmol) in THF (2 mL) was stirred at RT for 3 h.At this point, HPLC/MS indicated that all starting material had beenconsumed. Volatiles were removed in vacuo and the reaction was acidifiedwith aqueous 1 N HCl. The aqueous phase was extracted with EtOAc (2×250mL); the combined organic extracts were dried (Na₂SO₄) and concentratedin vacuo to give the crude phenylacetic acid. To a solution of the crudeacid was added oxalyl chloride (10 mL of a 2 M solution in CH₂Cl₂ andthe reaction mixture was stirred at RT for 3 h. Volatiles were removedin vacuo to give Part B compound as a solid which was used in the nextreaction without further purification.

To a 0° C. solution of Meldrum's acid (980 mg; 678 mmol) and pyridine(1.0 mL; 10 mmol) in anhydrous CH₂Cl₂ (10 mL) was added dropwise asolution of Part B compound (2.0 g; 5.65 mmol) in CH₂Cl₂ (5 mL) over 2h. The reaction mixture was allowed to warm to RT and stirred at RT for2 h. The mixture was then acidified by addition of excess aqueous 2N HCland extracted with CH₂Cl₂ (2×25 mL). The combined organic extracts weredried (Na₂SO₄) and concentrated in vacuo to provide the crude Meldrum'sacid adduct. A solution of this crude product and aniline (600 μL) intoluene (10 mL) was refluxed for 3 h. The reaction was cooled to RT andwashed with aqueous 1N HCl. Volatiles were removed in vacuo to give PartC compound (2.50 g; 97%) as a yellow solid.

To a 0° C. solution of aqueous H₂SO₄ (0.60 mL of a 1.84 M solution; 1.10mmol) was added dropwise a solution of Part C compound (300 mg, 0.60mmol), NaNO₂ (64 mg; 1.0 mmol) and aqueous 1N NaOH (0.70 mL; 0.70 mmol)in THF (10 mL) over 20 min. The reaction mixture was stirred at RT for30 min, after which the precipitate was filtered off and washed with H₂Oto give a yellow solid. This material was chromatographed (SiO₂;hexane:EtOAc 5:1 to 3:1) to give Part D compound (250 mg; 84%) as ayellow solid.

A solution of benzylhydrazine.2HCl (41 mg; 0.21 mmol) and sodiumethoxide (200 μL of a 21% solution in EtOH; 0.42 mmol) in ethanol (5 mL)was stirred at RT for 2 h. Part D compound (100 mg; 0.21 mmol) andanhydrous MgSO4 (200 mg) were then added and the reaction mixture washeated at 80° C. in an oil bath for 16 h. TLC indicated that allstarting material had been consumed. Volatiles were removed in vacuo,and the residue (the crude triazole-anilide) was dissolved in2-ethoxyethanol (10 mL). This solution was added to a solution of KOH(1.0 g; 8 mmol) in 2-ethoxyethanol (20 mL) at 150° C. The reactionmixture was heated at 150° C. for 30 min. HPLC/MS indicated that all ofthe anilide had been consumed at this point. The reaction mixture wascooled to RT, acidified with excess aqueous 1N HCl, and extracted withEtOAc (3×). The combined organic extracts were dried (Na2SO4) andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCreverse-phase ODS 30×250 mm column; flow rate=25 mL/min; 30 mincontinuous gradient from 30:70 B:A to 100% B+10 min hold-time at 100% B,where solvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (61 mg; 58%) as a white solidafter stripping from MeOH. [M+H]⁺=495.0.

¹H NMR (DMSO; 400 MHz) 2.34 (s, 3H), 2.87-2.92 (t, J=6.6 Hz, 2H),4.14-4.17 (m, 4H), 5.65 (s, 2H), 6.82-6.85 (d, J=8.76 Hz, 2H), 7.09-7.11(d, J=8.32 Hz, 2H), 7.26-7.40 (m, 5H), 7.42-7.55 (m, 3H), 7.94-7.97 (m,2H).

EXAMPLE 6

The procedure of Example 5 was employed to prepare the title compoundexcept that methyl 3-hydroxyphenyl-acetate was used as the startingmaterial in place of methyl 4-hydroxyphenyl-acetate. The title compound(6 mg) was obtained as a solid. [M+H]⁺=495.2.

EXAMPLE 7

A solution of Example 5 Part C compound (100 mg; 0.22 mmol),p-toluenesulfonyl azide (60 mg; 0.3 mmol) and Et₃N (50 μL; 0.3 mmol) inCH₂Cl₂ (3 mL) was stirred at RT for 3 h, at which point the reaction wascomplete by TLC. Volatiles were removed in vacuo, and the residue waschromatographed (SiO₂; stepwise gradient from 1:1 hex:EtOAc to EtOAc toCH₂Cl₂:MeOH:Et₃N 10:1:1) to provide Part A compound (100 mg; 95%) as ayellow solid.

A solution of Part A compound (100 mg; 0.21 mmol), benzylamine (30 μL;0.30 mmol) and TiCl₄ (300 μL of a 1 M solution in CH₂Cl₂; 0.30 mmol) in1,2 dichloroethane (5 mL) was heated at 88° C. in a sealed tube for 18h. At this point LC/MS showed the formation of the desired triazole. Thereaction mixture was cooled to RT and partitioned between EtOAc and H₂O(100 mL each). The organic phase was dried (Na₂SO₄) and concentrated invacuo to give the crude triazole-anilide as an oil. A mixture of thiscrude material and KOH (300 mg) was heated in EtOH (3 mL) at 80° C. for3 h. At this point, HPLC/MS showed that reaction was complete. Thereaction mixture was cooled to RT and partitioned between EtOAc andexcess aqueous 1 M HCl. The organic phase was washed with H₂O, dried(Na2SO4) and concentrated in vacuo. The residue was purified bypreparative HPLC (YMC reverse-phase ODS 30×250 mm column; flow rate=25mL/min; 30 min continuous gradient from 30:70 B:A to 100% B+10 minhold-time at 100% B, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solventB=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (48 mg; 46%) as asolid. [M+H]⁺=495.1

EXAMPLE 8

The synthetic sequence described in Example 7 was used for thepreparation of the title compound except that the corresponding1,3-substituted intermediate diazo-β-ketoamide

was used instead of the Example 7 Part A 1,4-substituted intermediate.This 1,3-substituted intermediate was prepared according to theprocedure described for the synthesis of Example 5 Part C compound,except that methyl 3-hydroxyphenylacetate was used instead of methyl4-hydroxyphenylacetate. [M+H]⁺=495.2.

EXAMPLES 9 AND 10

The procedures of Examples 7 and 8 were employed to prepare thefollowing analogs:

EXAMPLE 11

To a 0° C. solution of 4-hydroxybenzaldehyde (1.70 g, 12.3 mmol),5-phenyl-2-methyl-oxazole-4-ethanol (Maybridge; 2.50 g, 14.0 mmol) andPh₃P (4.20 g, 16.0 mmol) in dry THF (30 mL) was added dropwise DEAD(3.20 g, 15.0 mmol). The solution was stirred at 0° C. for 0.5 h, thenwas allowed to warm to RT and stirred overnight. The orange-red solutionwas concentrated in vacuo and the residue was chromatographed (stepwisegradient from 5:1 to 5:2 hex:EtOAc) to give Part A compound (2.47 g,65%) as a clear, slightly yellow viscous oil.

Alternative Procedure for Preparing Part A aldehyde:

To a −5° C. solution of 5-phenyl-2-methyl-oxazole-4-ethanol (20.00 g,0.098 mol) in CH₂Cl₂ (100 mL) was added methanesulfonyl chloride (12.40g, 0.108 mol) in one portion (exothermic reaction). After recooling to−5° C., Et₃N (11.1 g, 0.110 mol) was added slowly over 30 min (internaltemperature <3° C.). The reaction was allowed to warm to RT and stirredfor 1 h (reaction monitored by analytical HPLC), at which point startingmaterial had been consumed. The reaction was washed with aqueous HCl(2×50 mL of a 3N solution). The combined aqueous layers were extractedwith CH₂Cl₂ (50 mL). The combined organic extracts were successivelywashed with satd. aqueous NaHCO₃ and brine (50 mL each), dried (Na₂SO₄),and concentrated to ˜30 mL volume. Methyl tert-butyl ether (120 mL) wasadded and the mixture was stirred; a white solid was formed. The mixturewas cooled to −20° C. for complete crystallization. The product wasfiltered and vacuum-dried to give the product mesylate (23.3 g, 85%) asa white solid. The mother liquor was concentrated in vacuo andrecrystallized from methyl tert butyl ether/heptane to give a secondcrop of product mesylate (3.3 g, 12%; total yield=97%).

A mixture of the above mesylate (13.6 g, 0.048 mol),4-hydroxybenzaldehyde (7.09 g, 0.058 mol) and K₂CO₃ (9.95 g, 0.072 mol)in DMF (110 mL) was heated at 100° C. for 2 h (reaction complete byanalytical HPLC). The mixture was allowed to cool to RT and then pouredinto ice-water (400 mL) and stirred for 30 min. The solid product wasfiltered and washed with cold water (3×25 mL) and dried in vacuo at50°-60° C. overnight. The crude product was crystallized from methyltert-butyl ether/hexane to give (12.2 g, 82%; 2 crops) of Part Acompound as a white solid.

To a −78° C. solution of ethyl propiolate (256 mg; 2.6 mmol) in THF (12mL) was added dropwise n-butyllithium (1.04 mL of a 2.5 M solution inhexane; 2.6 mmol). The solution was stirred at −78° C. for 30 min; asolution of Part A aldehyde (800 mg; 2.6 mmol) in THF (3 mL) was thenadded dropwise. The reaction was stirred at −70° C. for 1 h, thenquenched by dropwise addition of saturated aqueous NH₄Cl. The mixturewas allowed to warm to RT, then extracted with EtOAc. The organic phasewas washed with H₂O, dried (Na₂SO₄) and concentrated in vacuo to givecrude Part B compound as an oil, which was used in the next step withoutfurther purification.

To a 0° C. solution of the crude Part B compound from above in dry MeCN(5 mL) were successively added Et₃SiH (620 μL; 3.97 mmol) and BF₃.OEt₂(384 μL; 3.1 mmol). The reaction mixture was allowed to warm to RT andstirred at RT for 2 h, at which point analytical HPLC showed that allstarting material had been consumed. Volatiles were removed in vacuo andthe residue was partitioned between H₂O and EtOAc. The organic phase waswashed with aqueous NaHCO₃ and then concentrated in vacuo. The crudeproduct was chromatographed (SiO₂; 4:1 hexane:EtOAc) to give Part Ccompound (514 mg; 50% over 2 steps) as white crystals.

A mixture of Part C compound (233 mg; 0.60 mmol) and phenyl azide (2 mL;prepared from aniline according to the procedure in Organic SynthesesCollective Volume IV, p. 75-77) in toluene (50 mL) was heated in asealed tube at 130° C. for 18 h. The mixture was cooled to RT andconcentrated in vacuo. The brown residue was chromatographed (SiO₂;stepwise gradient from 4:1 to 2:1 hexane:EtOAc) to give Part D compound(50 mg; 16%) as well as the isomeric product Part E compound

(100 mg; 32%) as a solid. [M+H]⁺=509.0

A solution of Part D compound (50 mg; 0.098 mmol) and aqueous 1 M LiOH(1 mL; 1.0 mmol) in THF (5 mL) was stirred at RT overnight. The reactionwas acidified with 1 M HCl (2 mL; 2.0 mmol) and extracted with EtOAc(2×). The combined organic extracts were washed with H₂O andconcentrated in vacuo. The residue was purified by preparative HPLC togive the title compound as a white solid (38 mg; 13% for 2 steps).[M+H]⁺=481.2

EXAMPLE 12

A solution of Example 11 Part E compound (50 mg; 0.098 mmol)

and aqueous 1 M LiOH (1 mL; 1.0 mmol) in THF (5 mL) was stirred at RTovernight. The reaction was acidified with 1 M HCl (2 mL; 2.0 mmol) andextracted with EtOAc (2×). The combined organic extracts were washedwith H₂O and concentrated in vacuo. The residue was purified bypreparative HPLC to give the title compound as a white solid (80 mg; 26%for 2 steps). [M+H]⁺=481.1

EXAMPLE 13

This intermediate was prepared employing the Example 11 Part A procedurefor the corresponding 1,4 derivative except that 3-hydroxybenzaldehydewas used as starting material instead of 4-hydroxybenzaldehyde.

To a −78° C. solution of ethyl propiolate (256 mg; 2.6 mmol) in THF (12mL) was added dropwise n-butyllithium (1.04 mL of a 2.5 M solution inhexane; 2.6 mmol). The solution was stirred at −78° C. for 30 min; asolution of Part A aldehyde (800 mg; 2.6 mmol) in THF (3 mL) was thenadded dropwise. The reaction was stirred at −70° C. for 1 h, thenquenched by dropwise addition of saturated aqueous NH₄Cl. The mixturewas allowed to warm to RT, then extracted with EtOAc. The organic phasewas washed with H₂O, dried (Na₂SO₄) and concentrated in vacuo to givecrude Part B compound as an oil, which was used in the next step withoutfurther purification.C. and D.

A mixture of Part A compound (230 mg; 0.57 mmol) and phenyl azide (2 mL;prepared from aniline according to the procedure in Organic SynthesesCollective Volume IV, p. 75-77) in toluene (50 mL) was heated in asealed tube at 130° C. for 18 h. The mixture was cooled to RT andconcentrated in vacuo. The brown residue was chromatographed (SiO₂;stepwise gradient from 4:1 to 2:1 hexane:EtOAc) to give Part C compound(70 mg; 23%) as well as the isomeric product Part D compound

(75 mg; 25% over 2 steps).

A solution of Part C compound (45 mg; 0.085 mmol) and aqueous 1 M LiOH(1 mL; 1.0 mmol) in THF (5 mL) was stirred at RT for 24 h. The reactionwas acidified with 1 M HCl (2 mL; 2.0 mmol) and extracted with EtOAc(2×). The combined organic extracts were washed with H₂O andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCreverse phase ODS 30×250 mm column; continuous 30 min gradient from70:30 A:B to 100% B, where solvent A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA; flow rate=25 mL/min) to give the titlecompound as a white solid (34 mg; 80%).

[M+H]⁺=497.1

EXAMPLE 14

A solution of Example 13 Part D compound (45 mg; 0.085 mmol) and aqueous1 M LiOH (1 mL; 1.0 mmol) in THF (5 mL) was stirred at RT overnight. Thereaction was acidified with 1 M HCl (2 mL; 2.0 mmol) and extracted withEtOAc (2×). The combined organic extracts were washed with H₂O andconcentrated in vacuo. The residue was purified by preparative HPLC(conditions as for the purification of Example 13 compound) to give thetitle compound (32 mg; 75%) as a white solid. [M+H]⁺=497.1

EXAMPLE 15

To a 0° C. solution of Example 13 Part C compound (35 mg; 0.067 mmol) indry MeCN (2.5 mL) were successively added Et₃SiH (12 mg; 0.10 mmol) andBF₃.OEt₂ (14 mg; 0.10 mmol). The reaction mixture was allowed to warm toRT and stirred at RT for 2 h, at which point analytical HPLC showed thatall starting material had been consumed. Volatiles were removed in vacuoand the residue was partitioned between H₂O and EtOAc. The organic phasewas washed with aqueous NaHCO₃ and then concentrated in vacuo. The crudeproduct was hydrolyzed using 1 M aqueous LiOH/THF as described for thesynthesis of Examples 13 and 14 to give the title compound (26 mg; 80%over 2 steps) as a yellow solid. [M+H]⁺=481.1

EXAMPLE 16

To a solution of methyl cyanoacetate (26 g; 256 mmol) and sodiummethoxide in MeOH (152 mL of a 0.5 M solution; 76 mmol) was added4-methoxybenzyl chloride (10.0 g; 64 mmol) at RT over 1 h. The resultingmilky suspension was heated to reflux for 3 h, after which volatileswere removed in vacuo. The residue was partitioned between H₂O and Et₂O.The organic phase was washed with H₂O, dried (Na₂SO₄), and partiallyconcentrated in vacuo. A white solid precipitate was filtered off, andthe filtrate was concentrated in vacuo to give an oil. This crudematerial was purified by Kugelrohr distillation (b.p.=180° C. @ 0.3 mmHg) to give Part A compound (7.6 g; 54%) as a clear oil which at RTcrystallized as a white solid.

A solution of Part A compound (7.6 g; 35 mmol) and NaOH (4.4 g; 110mmol) in H₂O (50 mL) was stirred at RT for 1 h. The reaction mixture waspartitioned between Et₂O (50 mL) and concentrated HCl (12 mL). Theorganic phase was washed with water, concentrated in vacuo and dried(Na₂SO₄) to give Part B compound (7.1 g; 96%) as a residue which becamea white solid at RT.

A diazotized solution of aniline (prepared according to the procedure ofWalker, T. K., J. Chem. Soc., 1924, 1622-1625) in HCl was treated withNaOAc (338 mg; 4.9 mmol; to remove free HCl) followed by addition ofPart B compound (1 g; 4.9 mmol) at 0° C. (resulting in evolution ofCO₂). The reaction mixture was stirred at 0° C. for 24 h. A yellow syrupwas separated from the aqueous phase and dissolved in CH₂Cl₂. Theaqueous phase was extracted with CH₂Cl₂ (2×20 mL); the combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo to give Part Ccompound (40 mg; 7%) as an oil.

To a −78° C. solution of Part C compound (20 mg; 0.062 mmol) in CH₂Cl₂(2 mL) was added BBr₃ (20 mg; 0.079 mmol). The reaction was stirred at−78° C. and then allowed to warm to RT. Workup (details needed) gavePart D compound (20 mg) as a crude oil which was used in the nextreaction without further purification.

A mixture of Part D compound (20 mg; 0.064 mmol), the mesylate (30 mg;0.11 mmol)

K₂CO₃ (100 mg; 0.72 mmol) in MeCN (5 mL) was heated at 80° C. Workupgave crude Product E (20 mg) as an oil which was used in the next stepwithout further purification.

A solution of crude Product E and aqueous LiOH (1 mL of a 1M solution)in THF was stirred at RT overnight. The reaction was acidified with 1 MHCl (2 mL) and extracted with EtOAc (2×). The combined organic extractswere washed with H₂O and concentrated in vacuo. The residue was purifiedby preparative HPLC (as described for the purification of Example 13compound) to give the title compound (7 mg; 22%) as a white solid.[M+H]⁺=480.2

EXAMPLE 17

The following compound was prepared employing the procedure of Example16 except that in Part A 3-methoxybenzyl chloride was employed in placeof 4-methoxybenzyl chloride.

[M+H]⁺=480.2

EXAMPLE 18

To a 0° C. solution of Meldrum's acid (4.33 g; 30 mmol) and pyridine(7.0 mL; 100 mmol) in CH₂Cl₂ (100 mL) was added dropwise3-methoxyphenylacetyl chloride (5.0 g; 27 mmol) over 1 h. The resultantmixture was stirred at RT for 2 h, then partitioned between aqueous 2NHCl and CH₂Cl₂. The organic layer was dried (Na₂SO₄) and concentrated invacuo to give the crude adduct. This residue was dissolved in MeOH (20mL) and the solution was heated at reflux for 3 h. The reaction mixturewas cooled to RT, volatiles were removed in vacuo to give Part Acompound (5.0 g; 83%) as a clear oil.

A solution of Part A compound (1.0 g; 4.5 mmol), dimethyl formamidedimethyl acetal (600 mg; 5.0 mmol) in CH₂Cl₂ (2.5 mL) was stirred at RTfor 2 h. The reaction mixture was directly chromatographed (SiO₂;stepwise gradient from hexane:EtOAc 1:1 to EtOAc) to give Part Bcompound (400 mg; 32%) as an oil.

A solution of Part B compound (100 mg; 0.36 mmol), phenylhydrazine (40mg 0.38 mmol) and activated 4A molecular sieves (500 mg) was heated at100° C. for 10 h. At this point analytical LC-MS indicated that thereaction was complete. The reaction was cooled to RT, filtered, and thefiltrate was concentrated in vacuo. The residue was chromatographed(SiO₂; hexane:EtOAc 4:1) to provide Part C compound (90 mg; 77%) as aclear oil.

To a −78° C. solution of Part C compound (80 mg; 0.25 mmol) in CH₂Cl₂ (5mL) was added BBr₃ (124 mg; 0.50 mmol) dropwise. The reaction mixturewas stirred at −78° C. for 30 min, then allowed to warm to RT andstirred at RT for 2 h. Volatiles were removed in vacuo and the residuewas partitioned between EtOAc and H₂O (5 mL each). The aqueous phase wasextracted with EtOAc (2×). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo to give an oil (the phenol-acid).This material was re-esterified by stirring in a saturated solution ofHCl in MeOH (2 mL) for 2 h at RT. Volatiles were removed in vacuo andthe residue was chromatographed (SiO₂; hexane:EtOAc 3:1) to provide PartD compound (50 mg; 62%) as a clear oil.

The same alkylation procedure was followed as in Example 1 using Part Dcompound (50 mg; 0.16 mmol in place of Example 1 Part F compound), themesylate (68 mg; 0.24 mmol)

and K₂CO₃ (224 mg; 1.6 mmol) in MeCN (5 mL) to provide Product E (20 mg;25%) as a crude product which was used in the next step without furtherpurification.

A solution of crude Product E in THF and aqueous LiOH (2 mL of a 1 Msolution) was stirred at RT overnight. The reaction was acidified withexcess 1 M aqueous HCl to pH˜2; the aqueous layer was extracted withEtOAc (3×). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for the purification of Example 13 compound) to give the titlecompound (9 mg; 12%) as a white solid.

EXAMPLE 19

The method of Example 18 was used to synthesize the regioisomeric analogExample 19 except that 4-methoxyphenyl-acetyl chloride was used in placeof 3-methoxyphenylacetyl chloride in Part A.

[M+H]⁺=480.2

EXAMPLE 20

To a 0° C. solution of propargyl magnesium bromide in THF (50 mL of a0.5 M solution; 25 mmol) under an atmosphere of N₂ was added dropwise asolution of 3-anisaldehyde (1.36 g; 10 mmol) in THF (10 mL). Thereaction mixture was stirred at 0° C. for 3 h, then was allowed to warmto RT overnight, after which all starting material had been consumed(TLC). The reaction mixture was quenched by pouring cautiously intosaturated aqueous NH₄Cl (30 mL) and ice (30 mL). The aqueous mixture wasextracted with EtOAc (2×150 mL). The combined organic extracts werewashed with H₂O (3×150 mL), dried (Na₂SO₄), and concentrated in vacuo togive Part A compound (1.2 g; 79%) as an oil. This material was used inthe next step without further purification.

To a refluxing mixture of Part A compound (500 mg; 3.08 mmol), Et₃N(several drops) and CH₂Cl₂ (4 mL) was added a solution of diketene(ketene dimer; 336 mg; 4.0 mmol) in CH₂Cl₂ (1 mL) over 30 min. Afteraddition was complete, heating under reflux was continued for another 3h, after which the reaction mixture was cooled to RT. Volatiles wereremoved in vacuo, and the crude product was purified by vacuumdistillation to give Part B compound (450 mg; 59%) as a colorless oil(b.p.=112° C. @ 0.05 mm Hg).

To a 0° C. solution of Part B compound (450 mg; 1.83 mmol) in anhydrousCH₂Cl₂ (3 mL) was added dropwise a solution of SO₂Cl₂ (161 μL; 2.0 mmol)in anhydrous CH₂Cl₂ (1 mL) over 2 h. Nitrogen was being continuouslybubbled into the reaction mixture during this time. The reaction wasallowed to warm to RT and stirred at RT for 2 h. Additional CH₂Cl₂ (10mL) was added and the reaction was quenched by addition of excesssaturated aqueous NaHCO₃. The organic phase was separated, washed withH₂O (2×), dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; hexane:EtOAc 5:1) to give Part C compound (380mg; 68%) as a clear oil.

To a 0° C. solution of Part C compound (150 mg; 0.53 mmol) and sodiumacetate (82 mg; 1.0 mmol) in 70% aqueous MeOH (15 mL) was added a 0° C.solution of benzenediazonium chloride (generated from 50 μL aniline and69 mg of NaNO₂) slowly dropwise. The reaction was then allowed to warmslowly to RT and stirred at RT overnight. The reaction mixture waspartitioned between EtOAc and H₂O (50 mL each). The organic phase waswashed with H₂O (2×), dried (Na₂SO₄), and concentrated in vacuo. Theresidue was chromatographed (SiO₂; hexane:EtOAc 3:1) to give Part Dcompound (192 mg; 94%) as a clear oil.

A solution of Part D compound (192 mg; 0.56 mmol) and Et₃N (1 mmol) inanhydrous toluene (20 mL) was heated under reflux until all startingmaterial had been consumed (2 h; TLC). After cooling to RT, the mixturewas washed with aqueous 1N HCl (30 mL) and H₂O (3×20 mL), dried(Na₂SO₄), and concentrated in vacuo. The resulting oil waschromatographed (SiO₂; hexane:EtOAc 3:1) to give Part E compound (120mg; 69%) as an oil.

TMSCl (25 mg; 0.23 mmol) was added to a mixture of Part E compound (20mg; 0.06 mmol) and sodium iodide (34 mg; 0.23 mmol) in anhydrousacetonitrile (5 mL). The reaction mixture was heated to reflux for 2 hunder an N₂ atmosphere. After cooling to RT, water (2 mL) was added andthe mixture was stirred at RT for 10 min. EtOAc (10 mL) was added andthe organic phase was washed with aqueous 70% Na₂S₂O₃ (10 mL) and water,dried (Na₂SO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (as described for Example 13 compound) to give Part Fcompound (15 mg; 81%) as a white solid.

To a −78° C. solution of Part F compound (15 mg; 0.049 mmol) in CH₂Cl₂(3 mL) was added dropwise neat BBr₃ (200 μL; 2.1 mmol). The reactionmixture was allowed to warm slowly to RT and stirred at RT for 1 h. Thereaction was then cooled to −65° C. and MeOH (0.5 mL) was cautiouslyadded. The solution was allowed to warm to RT and stirred at RT for 30min. Volatiles were removed in vacuo and the residue was partitionedbetween EtOAc and water (10 mL each). The organic phase was dried(Na₂SO₄) and concentrated in vacuo to give Part G compound (15 mg; 99%)as an oil.

A mixture of Part G compound (15 mg; 0.051 mmol), K₂CO₃ (28 mg; 0.20mmol) and the mesylate (34 mg; 0.12 mmol)

in MeCN (20 mL) was heated at 100° C. for 18 h. HPLC/MS at this pointindicated that the reaction was complete at this point. The reaction wascooled to RT, then partitioned between EtOAc (150 mL) and H₂O (100 mL).The organic phase was washed with H₂O (2×100 mL), dried (Na₂SO₄), andconcentrated in vacuo to give the crude product. This material waschromatographed (SiO₂; 3:1 hexane:EtOAc) to give Part H compound (20 mg;59%) as an oil.

A solution of Part G compound (20 mg; 0.03 mmol) in aqueous LiOH (1.0 mLof a 1.0 M solution) and THF (5 mL) was stirred at 50° C. for 4 h.HPLC/MS at this point showed that the reaction was complete. Thereaction was partitioned between EtOAc (10 mL) and aqueous HCl (10 mL ofa 1N solution). The organic phase was washed with H₂O (3×20 mL), thenwas concentrated in vacuo. The residue was purified by preparative HPLC(as described for the purification of BMS-460193) to give the titlecompound (12 mg; 83%) as a solid. [M+H]⁺=480.5

EXAMPLE 21

A solution of the Example 11 Part C acetylenic ester (100 mg; 0.26 mmol)

and quinoline (2 μL; 0.014 mmol) in the presence of Lindlar's catalyst(10% Pd/C) in toluene (5 mL) was stirred under an atmosphere of H₂(balloon) for 1.5 h. HPLC/MS at this point showed that reaction wascomplete. The catalyst was removed by filtration through Celite® and thefiltrate was concentrated in vacuo to give the crude α,β unsaturatedester as an oil. This material was chromatographed (SiO₂; hex:EtOAc 3:1)to give Part A compound (50 mg; 49%) as an oil.

A solution of Part A compound (430 mg; 1.09 mmol) and tosylmethylisocyanide (216 mg; 1.09 mmol) in DMSO (3 mL) was added dropwise to a 0°C. suspension of NaH (65 mg of a 60% suspension in oil) in Et₂O (2 mL).The reaction was then allowed to warm to RT and stirred at RT for 15min, at which point the reaction was complete by analytical HPLC. Thereaction mixture was partitioned between EtOAc and saturated aqueousNH₄Cl. The aqueous phase was extracted with EtOAc (2×). The combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was chromatographed (SiO₂; hex:EtOAc 3:1) to give Part Bcompound (300 mg; 69%) as an oil.

A mixture of Part B compound (20 mg; 0.047 mmol), phenylboronic acid (7mg; 0.057 mmol), Cu(OAc)₂ (5 mg; 0.028 mmol) and 4A molecular sieves(200 mg) in Et₃N: pyridine:CH₂Cl₂ (2 mL of a 1:1:2 mixture) was heatedin a sealed tube at 70° C. for 3 days. Analytical HPLC showed that thereaction was 60% complete. The reaction was cooled to RT and partitionedbetween EtOAc and 1 M aqueous HCl. The aqueous phase was extracted withEtOAc (2×); the combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to give Part C compound as an oil, which was usedin the next step without further purification.

A solution of crude Part C compound and aqueous LiOH (2 mL of a 1Msolution) in THF:H₂O was stirred at 100° C. for 24 h. The reaction wascooled to RT, then acidified to pH 2 with aqueous 1 M HCl. The aqueousphase was extracted with EtOAc (2×); the combined organic extracts weredried (Na₂SO₄) and concentrated in vacuo to give the crude product. Thismaterial was purified by preparative HPLC (as described for thepurification of Example 13 compound) to give the title compound (8 μm;35%) as a white solid. [M+H]⁺=479.2

EXAMPLE 22

A mixture of 3-hydroxy phenylethanol (500 mg; 3.61 mmol), the mesylate(990 mg; 3.52 mmol)

and K₂CO₃ (2.0 g; 14 mmol) in MeCN (5 mL) was stirred at 90° C. for 5 h.At this point LC/MS showed that the reaction was complete. The reactionwas cooled to RT, solids were filtered off, and the filtrate was dilutedwith EtOAc (100 mL). The solution was successively washed with aqueous 1M HCl (10 mL), 1 M NaOH (10 mL) and H₂O (50 mL), dried (Na₂SO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; 2:1hex:EtOAc) to give Part A compound (1.0 g; 87%) as an oil.

To a solution of Part A compound (1.0 g; 3.10 mmol) in CH₂Cl₂ (20 mL)was added Dess-Martin periodinane (3.0 g; 7.1 mmol) and the mixture wasstirred at RT for 3 h. Volatiles were removed in vacuo and the residuewas partitioned between EtOAc (25 mL) and H₂O (25 mL). The organic phasewas dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; hex:EtOAc 3:1) to give Part B compound (227 mg;23%) as an oil.

A mixture of Part B compound (86 mg; 0.27 mmol) and methyl(triphenylphosphoranylidene) acetate (110 mg; 0.33 mmol) in toluene (2mL) was heated at 100° C. for 2 h. Analytical HPLC showed that thereaction was complete. Volatiles were removed in vacuo and the residuewas chromatographed (SiO₂; hex:EtOAc 3:1) to give Part C compound (110mg; 98%) as an oil.

A solution of Part C compound (101 mg; 0.27 mmol) and tosylmethylisocyanide (TosMIC; 53 mg; 0.27 mmol) in DMSO (1 mL) was added dropwiseto a 0° C. suspension of NaH (15 mg of a 60% suspension in oil) in Et₂O(1 mL). The reaction was then allowed to warm to RT and stirred at RTfor 15 min, at which point the reaction was complete by analytical HPLC.The reaction mixture was partitioned between EtOAc and saturated aqueousNH₄Cl. The aqueous phase was extracted with EtOAc (2×). The combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was chromatographed (SiO₂; hex:EtOAc 3:1) to give Part Dcompound (20 mg; 18%) as an oil.

A mixture of Part D compound (20 mg; 0.048 mmol), phenylboronic acid (7mg; 0.057 mmol), Cu(OAc)₂ (5 mg; 0.028 mmol) and 4A molecular sieves(200 mg) in Et₃N: pyridine:CH₂Cl₂ (2 mL of a 1:1:2 mixture) was heatedin a sealed tube at 70° C. for 3 days. Analytical HPLC showed that thereaction was 60% complete. The reaction was cooled to RT and partitionedbetween EtOAc and 1 M aqueous HCl. The aqueous phase was extracted withEtOAc (2×); the combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to give Part E compound as an oil, which was usedin the next step without further purification.

A solution of crude Part E compound and aqueous LiOH (2 mL of a 1Msolution) in THF:H₂O was stirred at 100° C. for 24 h. The reaction wascooled to RT, then acidified to pH ˜2 with aqueous 1 M HCl. The aqueousphase was extracted with EtOAc (2×); the combined organic extracts weredried (Na₂SO₄) and concentrated in vacuo to give the crude product. Thismaterial was purified by preparative HPLC (conditions used as describedfor the purification of Example 13 compound) to give the title compound(7 gm; 30% over 2 steps) as a white solid.

[M+H]⁺=479.2

EXAMPLES 23 TO 50

The following N-aryl pyrrole acids were synthesized according to one ofthe above methods:

Example No. Ar [M+H]⁺ 23 H 403.3 24

493.0 25

547.0 26

514.0 27

509.0 28

497.0 29

556.9 & 558.9 30

485.0 31

497.0 32

514.0 33

557.0 & 559.1 34

493.3 35

509.3 36

547.3

37 H 403.2 38

493.1 39

547.1 40

513.0 41

509.1 42

497.1 43

557.0 & 559.0 44

485.0 45

597.1 46

513.0 47

557.2 and 559.1 48

493.3 49

509.3 50

547.3

EXAMPLE 51

The identical synthetic sequence described in Example 1 as used (exceptthat 3-methylphenylhydrazine replaced phenylhydrazine) to prepare thetitle compound (1.2 mg; 24% overall yield for last 3 steps).

[M+H]⁺=495.1

EXAMPLE 52

To a −74° C. solution of Example 3 Part E compound (50 mg; 0.13 mmol) inanhydrous THF (2 mL) was added lithium diisopropylamide(LDA) (200 μL ofa 2 M solution in heptane/THF). The blue reaction solution was stirredat −74° C. for 1 h, then was warmed to RT and stirred at RT for 1 h,then cooled to −78° C. A solution of iodomethane (85 mg; 0.6 mmol) inTHF (0.5 mL) was added dropwise and the reaction was stirred at −78° C.for 2 h, then was allowed to warm to RT. The reaction was partitionedbetween saturated aqueous NH₄Cl (0.5 mL), H₂O and EtOAc (5 mL each). Theorganic phase was dried (Na₂SO₄) and concentrated in vacuo; the residuewas chromatographed (SiO₂; continuous gradient from 100% hex to 3:7hex:EtOAc) to give Part A compound (20 mg; 38%) as white crystals.

To a RT solution of Part A compound (20 mg; 0.05 mmol) in CH₂Cl₂ (2.0mL) was added dropwise BBr₃ (0.2 mL of a 1 M solution in CH₂Cl₂). Themixture was stirred at RT for 30 min, then concentrated in vacuo. Theresidue was stripped from MeOH (1 mL) and chromatographed (SiO₂; 3:1hex:EtOAc) to give Part B compound (13 mg; 68%) as white crystals.

A mixture of Part B compound (13 mg; 0.032 mmol), 5-methyl 2-phenyloxazole 4-ethanol mesylate (15 mg; 0.053 mmol; prepared as described inExample 11) and K₂CO₃ (500 mg; 3.6 mmol) in MeCN (2 mL) was heated atreflux in a sealed tube for 18 h, then cooled to RT and filtered. Thefiltrate was concentrated in vacuo; the residue was dissolved in EtOH (2mL) and KOH (200 mg; 3.6 mmol) was added. The mixture was stirred at 80°C. in a sealed tube, then cooled to RT and partitioned between EtOAc (20mL) and aqueous 1 N HCl (5 mL). The organic phase was washed with H₂O(2×10 mL) and concentrated in vacuo. The residue was purified bypreparative HPLC (YMC reverse-phase ODS 20×100 mm column; flow rate=20mL/min; 10 min continuous gradient from 25:75 B:A to 100% B +5 minhold-time at 100% B, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solventB=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (14.8 mg; 88%) as awhite solid.

[M+H]⁺=495.3

EXAMPLE 53

The procedure described for the synthesis of Example 52 Part A compoundwas used (except that Example 1 Part E compound [50 mg; 0.13 mmol] wasused in place of Example 3 Part E compound) to prepare Part A compound(35 mg; 68%) as an oil.

The synthetic sequence described for the synthesis of Example 52 (exceptthat Part A compound was used instead of Example 52 Part A compound) wasused to prepare the title compound (24 mg; 55% overall for 3 steps) as asolid.

[M+H]⁺=495.3

EXAMPLE 54

A solution of Example 22 Part B compound (150 mg; 0.47 mmol) andtert-butyl (triphenylphosphoranylidene)-acetate (200 mg; 0.53 mmol) intoluene (10 mL) was stirred at 90° C. for 1 h. After cooling, volatileswere removed in vacuo and the residue was chromatographed (SiO₂; 3:1hex:EtOAc) to give Part A compound (200 mg; 99%) as an oil.

A solution of Part A compound (200 mg; 0.477 mmol) and tosylmethylisocyanide (100 mg; 0.512 mmol) in DMSO was added dropwise into a slurryof NaH (26 mg of a 60% mixture in oil; 0.65 mmol) in Et₂O over 30 min atRT. The reaction was stirred at RT for 30 min, then was partitionedbetween H₂O and EtOAc. The organic phase was dried (Na₂SO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; hex:EtOAc3:1) to give Part B compound (60 mg; 27%) as an oil.

A mixture of Part B compound (23 mg; 0.05 mmol), K₂CO₃ (200 mg; 1.45mmol) and methyl iodide (10 mg; 0.07 mmol) in DMF (2 mL) was stirred at80° C. for 2 h in a sealed tube. The reaction was cooled to RT andpartitioned between H₂O and EtOAc (10 mL each). The organic phase waswashed with H₂O (2×10 mL), dried (Na₂SO₄) and concentrated in vacuo. Asolution of the crude N-methyl pyrrole ester in TFA/CH₂Cl₂ (2 mL of a1:1 solution) was stirred at RT for 30 min, then was concentrated invacuo. The residue was purified by preparative HPLC (according to theconditions for Example 52 compound, except that a continuous gradient of70:30 A:B to 100% B was used rather than 75:25 A:B to 100% B) to furnishthe title compound (7.2 mg; 34%) as a white solid.

[M+H]+=417.2

EXAMPLE 55

Part A compound was prepared as described for the synthesis of Example22 Part B compound from the mesylate

and 4-hydroxyphenylethanol (which was used instead of3-hydroxyphenylethanol).

Part A compound (150 mg; 0.47 mmol) was used to prepare (as describedfor the synthesis of Example 54 Part A compound) Part B compound (200mg; 99%) as an oil.

Part B compound (200 mg; 0.477 mmol) was used to prepare (as describedfor the synthesis of Example 54 Part B compound) Part C compound (100mg; 46%) as an oil.

Part C compound (23 mg; 0.05 mmol) was used to prepare (as described forthe synthesis of Example 54) the title compound (7.7 mg; 37%) as a whitesolid.

[M+H]+=417.2

EXAMPLE 56

A mixture of Example 54 Part B compound (20 mg; 0.044 mmol),2-bromothiophene (8 mg; 0.05 mmol), CuI (30 mg; 0.157 mmol), ZnO (10 mg;0.122 mmol) and K₂CO₃ (50 mg; 0.36 mmol) in 1-methyl-2-pyrrolidinone(NMP; 2 mL) was heated in a sealed tube at 166° C. for 18 h. Thereaction was cooled to RT and partitioned between EtOAc and aqueous HCl(10 mL of a 1 M solution). The organic phase was washed with brine (2×10mL), dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 1:1 hexane:EtOAc) to give Part A compound as asolid.

A solution of Part A compound in TFA/CH₂Cl₂ (1 mL of a 1:1 solution) wasstirred at RT for 1 h, then was concentrated in vacuo. The residue waspurified by preparative HPLC (according to the conditions described forExample 54 compound) to furnish the title compound (7 mg; 32% for 2steps) as a white solid.

[M+H]+=485.2

EXAMPLE 57

Example 55 Part C compound (20 mg; 0.044 mmol; using the same syntheticsequence as described for Example 56) was used to prepare the titlecompound (5 mg; 23%) as a solid.

[M+H]+=485.2

EXAMPLE 58

A mixture of Example 54 Part B compound (20 mg; 0.044 mmol),2-bromothiazole (10 mg; 0.061 mmol), CuI (30 mg; 0.157 mmol), ZnO (10mg; 0.122 mmol) and K₂CO₃ (50 mg; 0.36 mmol) in 1-methyl-2-pyrrolidinone(2 mL) was heated in a sealed tube at 166° C. for 18 h. The reaction wascooled to RT and partitioned between EtOAc and aqueous HCl (10 mL of a 1M solution). The organic phase was washed with brine (2×10 mL), dried(Na₂SO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; 1:1 hexane:EtOAc) to give Part A compound as a solid.

A solution of Part A compound in TFA/CH₂Cl₂ (1 mL of a 1:1 solution) wasstirred at RT for 1 h, then was concentrated in vacuo. The residue waspurified by preparative HPLC (according to the conditions described forExample 54) to furnish the title compound (9 mg; 42% for 2 steps) as abrown solid.

[M+H]+=486.3

EXAMPLE 59

Example 55 Part C compound (20 mg; 0.044 mmol; using the same syntheticsequence as described for Example 56) was used to prepare the titlecompound (5 mg; 23%) as a brown solid.

[M+H]+=486.3

EXAMPLE 60

A solution of Example 11 Part C compound (176 mg; 0.45 mmol) and sodiumazide (32 mg; 0.49 mmol) in anhydrous DMF (1 mL) was stirred at RT underan atmosphere of N₂ for 15 min, after which H₂O (10 mL) was added. Thesolids were filtered off and dried in vacuo, then chromatographed (SiO₂;3:1 hex:EtOAc) to give Part A compound (138 mg; 71%) as a yellow solid.

A solution of Part A compound (138 mg; 0.319 mmol), benzyl bromide (118mg; 0.69 mmol) and K₂CO₃ (238 mg; 2.05 mmol) in DMF (1 mL) was stirredat RT for 18 h. The reaction was partitioned between H₂O and EtOAc (5 mLeach); the organic phase was dried (Na₂SO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; hex:EtOAc 3:1) to give Part Bcompound (25 mg; 15%) as an oil. In addition, the other two regioisomerswere also obtained: Part C compound (40 mg; 23%)

and Part D compound (12 mg; 7%)

A solution of Part B compound in THF (2 mL) and aqueous LiOH (1 ML of a1 M solution) was stirred at RT for 18 h, then partitioned betweenaqueous HCl (2 mL of a 1 M solution) and EtOAc (5 mL). The organic phasewas washed with H₂O (2×5 mL), dried (Na₂SO₄) and concentrated in vacuoto give the title compound (19 mg; 80%) as a white solid.

[M+H]⁺=495.2

EXAMPLE 61

Example 54 Part B compound was used to prepare (as described for thesynthesis of Example 54, but using benzyl bromide instead of methyliodide) the title compound (7 mg) as a yellow solid after preparativeHPLC purification (as for Example 54).

[M+H]+=493.1

EXAMPLE 62

To a solution of benzaldehyde (23.8 g, 234 mmol) in EtOAc (150 mL;pre-saturated with HCl gas) was added 2,3-butanedione mono-oxime (25.0g, 234 mmol) in one portion and the resulting solution was stirred at RTfor 12 h. Analytical HPLC indicated that all starting materials had beenconsumed. The reaction mixture was concentrated in vacuo to yield Part Acompound as a white solid, which was used in the next step withoutfurther purification.

To a solution of Part A compound in CHCl₃ (200 mL) was added dropwisePOCl₃ (30 mL, 320 mmol). The reaction was stirred for 12 h at 50° C.,then was concentrated in vacuo. The brown residue was partitionedbetween EtOAc (300 mL) and 1N aqeuous NaOH. The organic phase was washedwith brine, dried, (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; Et₂O) to give Part B compound (41.5 g; 86%) as alight brown solid (>95% pure by analytical HPLC and ¹H-NMR analysis).

A mixture of Example 1 Part C compound (592 mg; 1.9 mmol) and3-methylphenylhydrazine (330 mg; 2.08 mmol) in EtOH (30 mL) andanhydrous MgSO₄ (1 g) was heated to reflux overnight. The reaction wasfiltered, and the filtrate was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAc)to give Part C compound (478 mg; 76%) as a mixture of S-cis and S-transoximes.

To a RT solution of Part C compound (103 mg; 0.31 mmol) in toluene (5mL) was added PCl₅ (70 mg; 0.34 mmol) and the reaction was stirred at RTfor 2 h, then concentrated in vacuo. The residue was partitioned betweenEtOAc and H₂O; the organic phase was washed with brine, dried (Na₂SO₄),and concentrated in vacuo to give crude Part D compound, which was usedin the next step without further purification.

To a RT solution of crude Part D compound in absolute EtOH (3 mL) wasadded dropwise aqueous NaOH (0.25 mL of a 2 M solution). The mixtureturned from orange to dark brown and was stirred at RT for 1 h, then waspartitioned between excess aqueous 1 N HCl and EtOAc. The aqueous phasewas extracted with EtOAc, and the combined organic extracts were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (as described for Example 5) to give Part Ecompound (10.5 mg; 11% for 2 steps) as a brown solid.

To a −78° C. solution of Part E compound (11 mg; 0.033 mmol) was addedBBr₃ (0.02 mL; 0.21 mmol) dropwise. The reaction was stirred at −78° C.for 15 min, then was warmed to RT and stirred at RT for 5 h. Aftercooling to 0° C., the reaction was cautiously quenched with a largeexcess of saturated aqueous NH₄Cl. The aqueous phase was extracted withEtOAc; the combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated in vacuo to give crude Part F compound, whichwas used in the next step without further purification.

A mixture of Part F compound (10 mg; 0.033 mmol), K₂CO₃ (15 mg; 0.11mmol) and Part B compound (20 mg; 0.096 mmol) in MeCN (2 mL) was heatedat 90° C. overnight, then cooled to RT and partitioned between H₂O andEtOAc. The aqueous phase was extracted with EtOAc; the combined organicextracts were washed with brine, dried (Na₂SO₄), and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from100% hexane to 100% EtOAc) and then further purified by preparative HPLC(conditions as for purification of Example 52, except that a continuousgradient from 30:70 A:B to 100% B was used) to provide the titlecompound (5.2 mg; 26% for 2 steps) as a colorless oil.

[M+H]+=481.1

Following the procedures set out in the above Examples and in thereaction schemes, the following exemplary compounds may be prepared:

EXAMPLE 63 In Vitro Screening Assays for Dual PPARγ Antagonist/PPARαAgonist

A. Screen for PPARγ Antagonist in Mouse 3T3-L1 Pre-adipocyte Cells

Compounds which show potent binding to PPARγ were assayed for theirability to inhibit 50 nM rosiglitazone (an authentic PPARγ agonist)induced differentiation of mouse 3T3-L1 pre-adipocytes to matureadipocytes. 5×10⁵ 3T3-L1 cells per plate were added to 96 well platesand cultured in DMEM-high glucose and 10% FBS medium for two days beforeinduction. Cells were induced for 48 hr with 1 μm dexamethasone, 5 μg/mlinsulin, and 0.6 μm isobutylmethylxanthine (IBMX) in the same medium. Atthis time, test compounds in a serial dilution were added into 50 nMrosiglitazone and 0.1% DMSO containing medium in each well. Cells werere-fed with the same concentration of testing compound, rosiglitazone (aPPARγ agonist) and DMSO containing medium (without insulin,dexamethasone and IBMX) for an additional 72 hr. After a total of 5 daysincubation, 4 μl of media from each well were collected and diluted into40 μl of H₂O in 96 well ELISA plate, 300 μl of Triglycerides BlankReagent (Bayer Diagnostics) was added into each well and incubated for 5min at room temperature. The % inhibition of each compound torosiglitazone induced free glycerol release from the cell was determinedusing Spectremax 250 ELISA reader at wavelength 500 nM. Data werenormalized to DMSO only control and % maximum inhibition oftransactivation was calculated relative to 50 nM rosiglitazone positivecontrol. The ED₅₀ values were calculated using standard equations formid-point of the activity inhibition curves.

B. Screen for PPARγ Antagonist in CV-1 Primate Kidney Cells

Compounds which show potent binding to PPARγ were assayed for theirability to inhibit 1 μM rosiglitazone (an authentic PPARγ agonist)induced transactivation of SEAP reporter gene activity in CV-1 cells.CV-1 cells (these cell express endogenous PPARγ gene) were transfectedwith a 3×PPRE-SEAP reporter gene DNA construct and stable colonies wereselected, expanded and tested for responsiveness to compounds usingstandard protocols. SEAP reporter gene constructs were made by inserting3 repeats of the rat fatty acid binding protein PPRE including the 7nucleotides immediately 5′ to the SV40 early minimal promoter of pSEAP2(Clontech). 1.2×10⁶ CV-1/PPRE-SEAP cells were plated in a 96 well plateone day before compound addition. Dilution series of test compounds weremade in DMEM 10% FBS, 0.5% (v/v final) DMSO and 1 uM rosiglitazone (aPPARγ agonist). 150 μl aliquots of each concentration were delivered totwo non-adjacent wells. Also included on each plate were 6 wells of 1 μMrosiglitazone (a PPARγ agonist) in 0.5% DMSO media. Media was collectedin fresh 96 well plates 40 hrs following incubation with compounds andassayed for SEAP activity. SEAP is resistant to heat, so the endogenousphosphatases in the collected media were inactivated by sealing theplates with pressure sensitive adhesive sealing film (Corning), andheating at 65° C. for 30′ to 1 hour. After allowing to come to roomtemperature (RT), 25 μl of aliquots of heat inactivated media were addedto clear bottom 96 well black plates, 100 μl of the fluorescentsubstrate Attophos reagent (Promega) was added per well. The plate wasincubated for 5′ in the dark, and then the fluorescence measured in aCytoFluor series 4000 plate reader (Perseptive Biosystems): excitationfilter, 450/50 nm; emission filter, 580/50 nm; 8 cycles, 1 minute/cycle,3 reads/well/cycle. Data were normalized to DMSO only control and %maximum inhibition of transactivation was calculated relative to 1 μmrosiglitazone positive control. The ED₅₀ values were calculated usingstandard equations for mid-point of the activity inhibition curves.

C. Screen for PPARα Agonist in HepG2 Human Liver Cells

Compound which show potent binding to PPARα were tested for theirability to stimulate PPARα dependent stimulation of reporter geneactivity in HepG2, human liver derived, cells which express endogenousPPARα gene, or HepG2 cells stably expressing a Gal-4 DNA bindingdomain-PPARα ligand binding domain chimeric receptor (described below).Reporter gene constructs were made by inserting either 3 repeats of therat fatty acid binding protein PPRE including the 7 nucleotidesimmediately 5′, or 4 repeats of the gal4 response element upstream ofthe SV40 early minimal promoter of p-SEAP2 (Clontech), 3×PPRE-SEAP andgal4-SEAP respectively. The chimeric receptor was made by cloning thecDNA encoding the ligand binding domain of human PPAR α in frame and 3′to the gal4 DNA binding domain (amino acids 1-47) in the mammalianbicistronic expression vector pIRES1neo (Clontech), gal4-PPAR α. Stablecell lines were generated by transfection with both gal4-SEAP andgal4-PPARα or with 3×PPRE-SEAP, using Lipofectamine Plus (Gibco)following the manufacturer's directions. Cells were plated onto 96 wellplates and allowed to adhere overnight. The next day, serial dilutionsof the compounds in growth media (DMEM plus 10% charcoal/dextranstripped FBS) containing 0.5% (v/v) DMSO, were added in duplicate tonon-adjacent wells, and allowed to incubate for 24-40 hours at 37° C.,5% CO2. Each plate had at least 6 wells of 1 μM standard, GW-2331 (anauthentic PPARα selective agonist) as positive control, rosiglitazone(an authentic PPARγ agonist) as negative control and 3 wells of DMSOalone media as control. Following the incubation, media was removed, andendogenous phosphatases were inactivated as indicated above and SEAPactivity in 25 μl aliquots of processed media was assayed in clearbottom, black 96 well plate (Falcon) by the addition of 100 μl Attophosreagent (Promega), incubation for 5 minutes in the dark at roomtemperature, and measuring the increase in fluorescence (excitation 450nm, emission 580 nm) in a CytoFluor series 4000 plate reader (PerseptiveBiosystems) 8 cycles, 1 minute/cycle. The relative rates of fluorescenceemission were calculated as fold increase over DMSO control. Intrinsicactivity was defined as the activity of the test compound at 1 μM as %of activity of the 1 μM standard. The EC₅₀ values were calculated usingstandard equations for mid-point of the activity curves.

EXAMPLE 64 In Vivo Obese Animal Model

C57BL/6 mice were fed a diet rich in fat (40%) and sucrose (40%) (see,York {Genetic models of obesity} and Sclafani (Dietary models ofobesity}, both in Obesity, Bjorntorp and Brodoff eds. J B LippincottCompany, 1992; McIntosh and Pederson; McNeill. eds. CRC press LLC,337-398, 1999; Farrelly et al., Proc. Natl. Acad. Sci. 96: 14511-14516,1999). Under these dietary conditions, C57BL/6 mice gain considerablebody weight and become obese. These mice were treated with a dual PPARγantagonist/PPARα agonist (dose 0.01 to 100 mg/kg/day), administered in apharmacologically acceptable vehicle (such as but not limited to, 5%CM-cellulose) through orally, intravenous, subcutaneous or intraportalinjection, or mixed with food or water, acutely or over an extendedperiod of time. During the course of the study, various parameters suchas water and food consumption, body weight gain, body composition bydual emission X-ray analyzer (DEXA, this instrument accurately measuresbody fat mass, body lean muscle mass and body bone mineral content),body temperature was measured by standard methods. Through tail veinbleeding, blood was collected in heparin-EDTA coated tubes to preventclotting and blood plasma was separated and analyzed for glucose, freefatty acids, triglycerides and cholesterol using reagent kits availablefrom Roche Diagnostics in a COBAS-MIRA instrument. Insulin and leptinare measured by commercially available ELISA kits. Compounds that act toreduce body weight and or decrease glucose were selected. At the end ofthe treatment period animals were euthanized by brief exposure to CO₂and internal organs such as liver and white adipose tissue wereharvested for additional analysis. These analyses may include, but notlimited to, determination of lipid content, and effect on various PPARγand PPARα target gene expression.

Test compounds that reduce body fat mass, body lean mass, prevent orameliorate obesity, insulin resistance, are also tested in the diseasemodels described above, in combination with an anti diabetic agent suchas but not limited to metformin and sulfonylurea and/or a lipid loweringagent such as PPARα agonists (such as, but not limited to fenofibrateand gemfibrozil) and/or HMG CoA reductase inhibitors (such as, but notlimited to, pravastatin, lovastatin, simvastatin and atorvastatin).During the course of the study various parameters such as water and foodconsumption, body weight gain, body temperature and plasma glucose,insulin, free fatty acids, triglycerides and cholesterol levels weremeasured. Compounds that act to reduce body fat mass increase body leanskeletal mass, body weight and or decrease glucose, and lipids wereselected for further characterization.

EXAMPLE 65

A solution of Example 1 compound (31 mg; 0.065 mmol), oxalyl chloride(0.50 mL of a 2.0 M solution in CH₂Cl₂; 1.0 mmol) and DMF (1 drop) washeated at 60° C. in a sealed tube overnight, then was cooled to RT andconcentrated in vacuo to give the crude acid chloride. A solution ofdiazomethane was prepared by portionwise addition of1-methyl-3-nitro-1-nitrosoguanidine (440 mg; 3 mmol) to a 0° C. solutionof Et₂O (2 mL) and 40% aqueous KOH (1.3 mL); after standing for 30 min,the organic phase (containing diazomethane) was dried (solid KOH) andused immediately. The crude acid chloride was dissolved in the 0° C.solution of ethereal diazomethane and was allowed to stand for 30 min at0° C., then at RT for 2 h. Excess diazomethane in the reaction wasquenched with acetic acid; volatiles were then removed in vacuo. Theresidue was chromatographed (SiO₂; hex:EtOAc 3:1) to give Part Acompound (22 mg; 67%) as a yellow oil.

To a solution of Part A compound (22 mg; 0.044 mmol) in anhydrous MeOH(1 mL) were successively added silver benzoate (9 mg; 0.04 mmol) andanhydrous Et₃N (35 μL; 0.25 mmol). The reaction was stirred at RT for 45min (color became dark), then was partitioned between EtOAc and H₂O (10mL each). The organic phase was successively washed with H₂O, 1 Naqueous HCl and 1 N aqueous NaOH (each 10 mL), then was concentrated invacuo. The residual crude methyl ester was dissolved in THF (2 mL) andaqueous LiOH (2 mL of a 1 N solution) and the reaction was stirred at RTovernight. The reaction mixture was partitioned between EtOAc andaqueous 1 N HCl (10 mL each); the organic phase was washed with H₂O(2×10 mL), then was concentrated in vacuo. The residue was purified bypreparative HPLC (YMC ODS 30×250 mm reverse phase column; flow rate 25mL/min; 30 min continuous gradient from 70:30 A:B to 100% B; A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA; detection at 220 nm) to give thetitle compound (8 mg; 36%) as white crystals.

[M+H]⁺=495.3 ¹H NMR(CDCl₃): δ 2.38 (3H, s), 2.94 (2H, t, J=7.9 Hz), 3.68(2H, s), 4.12 (2H, s), 4.26 (2H, t, J=7.9 Hz), 6.75 (1H, m), 6.90 (1H,s), 6.98 (1H, d, J=8 Hz), 7.22 (1H, t, J=7.9 Hz), 7.28 (1H, t, J=7.5Hz), 7.41-7.48 (5H, m), 7.96-8.02 (4H, m)

EXAMPLE 66

A mixture of 3-(3-methoxyphenyl) propionic acid (1.0 g; 5.55 mmol) andoxalyl chloride (3.0 mL of a 2 M solution in CH₂Cl₂; 6.0 mmol) in CH₂Cl₂(5 mL) was heated in a sealed tube at 60° C. for 2 h, then cooled to RTand concentrated in vacuo to give Part A compound as an oil which wasused without further purification in the next step.

To a 0° C. solution of Meldrum's acid (960 mg; 6.7 mmol) and pyridine(1.6 mL; 20 mmol) in CH₂Cl₂ (5 mL) was added dropwise Part A compound(1.20 g; 6.0 mmol) in CH₂Cl₂ (3 mL) over 30 min. The resultant mixturewas stirred at RT for 2 h, then partitioned between aqueous 2 N HCl andCH₂Cl₂. The organic layer was dried (Na₂SO₄) and concentrated in vacuoto give crude Part B compound as an oil. This material was used in thenext step without further purification.

A solution of the crude Part B compound and aniline (910 μL; 10 mmol) inanhydrous toluene (10 mL) was heated to reflux for 3 h. The reactionsolution was then washed with aqueous 1 M HCl, then concentrated invacuo to give Part C compound (1.29 g; 78%) as a yellow oil.

To a 0° C. aqueous solution of H₂SO₄ (640 μL of a 1.84 M solution; 12mmol), H₂O (2 mL) and THF (7 mL) was added dropwise over 20 min asolution of Part C compound (1.29 g; 4.34 mmol), NaNO₂ (450 mg; 6.5mmol) and aqueous 1 M NaOH (4.34 mL; 4.34 mmol). The reaction mixturewas stirred at 0° C. for 2 h, then was partitioned between EtOAc and H₂O(20 mL each). The organic phase was washed with H₂O (2×20 mL), dried(Na₂SO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; 3:1 hex:EtOAc) to give Part D compound (780 mg; 55%) as yellowcrystals.

A solution of Part D compound (729 mg; 2.23 mmol), phenylhydrazine (0.30mL; 3.0 mmol) and MgSO₄ (2 g) was refluxed in EtOH (5 mL) for 18 h, thenwas cooled to RT and partitioned between EtOAc and H₂O (20 mL each). Theorganic phase was washed with H₂O (2×20 mL), dried (Na₂SO₄) andconcentrated in vacuo. The residue was crystallized from hexane/CH₂Cl₂(1:1) to provide Part E compound (676 mg; 73%) as yellow crystals.

A solution of Part E compound (300 mg; 0.720 mmol) and TFAA (141 μL; 1.0mmol) in CH₂Cl₂ was heated in a sealed tube at 45° C. for 2 h. At thispoint starting material had been consumed by analytical HPLC. Volatileswere removed in vacuo. The residue was chromatographed (SiO₂; 3:1hex:EtOAc) to give Part F compound (280 mg; 98%) as a yellow oil.

To a −70° C. solution of Part F compound (260 mg; 0.652 mmol) in CH₂Cl₂(1 mL) was added dropwise BBr₃ (1.0 mL of a 1 M solution in CH₂Cl₂). Themixture was allowed to warm to RT and stirred at RT for 2 h, then wasconcentrated in vacuo. The residue was partitioned between EtOAc and H₂O(10 mL each). The organic phase was washed with H₂O (2×10 mL), dried(Na₂SO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; 3:1 hex:EtOAc) to give Part G compound (98 mg; 39%) as yellowcrystals.

A mixture of Part G compound (28 mg; 0.073 mmol), 5-methyl 2-phenyloxazole 4-ethanol mesylate (70 mg; 0.25 mmol; prepared as described inExample 11) and K₂CO₃ (138 mg; 1.0 mmol) in MeCN (5 mL) was stirred at80° C. for 18 h, then was cooled to RT and partitioned between EtOAc andH₂O (20 mL each). The organic phase was washed with H₂O (2×20 mL), dried(Na₂SO₄) and concentrated in vacuo to give crude Part H compound, whichwas used in the next reaction without further purification.

A solution of crude Part H compound and KOH (400 mg; 7.12 mmol) in EtOH(5 mL) was heated at 150° C. in a sealed tube for 3 h, then was cooledto RT and concentrated in vacuo. The residue was partitioned betweenEtOAc and 1 M aqueous HCl (20 mL each). The organic phase was washedwith H₂O (20 mL), dried (Na₂SO₄) and concentrated in vacuo. The residuewas purified by preparative HPLC (Phenomenex LUNA 5 g C18 21.2×100 mmreverse phase column; flow rate 25 mL/min; 8 min continuous gradientfrom 70:30 A:B to 100% B; A=90:10:0.1 H₂O:MeOH:TFA; B=90:10:0.1MeOH:H₂O:TFA; detection at 220 nm) to give the title compound (12 mg;33% over 2 steps) as a solid.

[M+H]⁺=495.3 ¹H NMR (CDCl₃): δ 2.45 (3H, s), 3.05-3.10(4H, m), 3.39 (2H,t, J=7.9 Hz), 4.26 (2H, t, J=7.9 Hz), 6.69-6.75 (2H, m), 6.91 (1H, S),7.11 (1H, t, J=7.9 Hz), 7.37 (1H, t, J=1.8 Hz), 7.45-7.55 (5H, m),7.96-8.02 (4H, m) ¹³C NMR (CDCl₃): δ 163.4, 160.2, 158.4, 152.2, 146.9,142.35, 139.2, 137.7, 132.2, 130.1, 129.3, 129.2, 128.4, 126.9, 124.2,121.6, 119.4, 114.1, 113.4, 66.1, 35.2, 26.7, 24.8, 10.2.

EXAMPLE 67

A solution of 3-(3-hydroxyphenyl)propanoic acid (3.01 g; 18.1 mmol) andconcentrated sulfuric acid (0.5 mL) in MeOH (25 mL) was heated in an oilbath at 55° C. for 1 h. Volatiles were removed in vacuo and the mixturewas neutralized with excess aqueous NaHCO₃, then was partitioned betweenEtOAc and H₂O. The organic phase was washed with brine, dried (MgSO₄)and concentrated in vacuo to give Part A compound (3.12 g; 96%) as ayellow oil.

A mixture of Part A compound (3.12 g; 17.3 mmol), 5-methyl 2-phenyloxazole 4-ethanol mesylate (4.86 g; 17.3 mmol; prepared as shown inExample 11) and K₂CO₃ (4.9 g; 36 mmol) in MeCN (100 mL) was heatedovernight at 90° C. in an oil bath. Volatiles were removed in vacuo, andthe residue was partitioned between H₂O and EtOAc. The aqueous phase wasextracted with EtOAc (2×) and the combined organic extracts were dried(MgSO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; continuous gradient from 100% hex to 100% EtOAc) to give theproduct, which still contained some unreacted phenol starting material.The product was washed repeatedly with aqueous 2N NaOH to furnishpurified Part B compound (4.0 g; 63%) as an oil.

To a 0° C. solution of Part B compound (2.02 g; 5.55 mmol) in anhydrousTHF (30 mL) was cautiously added portionwise solid LiAlH₄ (290 mg; 7.63mmol). The reaction mixture was allowed to warm to RT, stirred at RTovernight, then was cautiously quenched with excess aqueous 1 N HCl. Themixture was extracted with EtOAc (2×). The combined organic extractswere washed with brine, dried (Na₂SO₄) and concentrated in vacuo to givePart C compound (1.90 g; 100% crude), which was used in the nextreaction without further purification.

To a RT suspension of Dess-Martin periodinane (3.6 g; 8.5 mmol) inCH₂Cl₂ (50 mL) was added dropwise a solution of Part C compound (1.90 g;5.64 mmol) in CH₂Cl₂ (10 mL) over 5 min. The reaction was stirred at RTfor 4.5 h, then was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAc)to give Part D compound (1.70 g; 90%) as a colorless oil.

To a −78° C. suspension of NaH (65 mg of a 60% mixture; 8.13 mmol) inanhydrous THF (10 mL) under N₂ was added (CF₃CH₂O)₂P(O)CH₂CO₂CH₃ (380μL; 1.79 mmol) dropwise. The solution was stirred at −78° C. for 10 min,after which a solution of Part D compound (343 mg; 1.02 mmol) in THF (5mL) was added dropwise over 5 min. The reaction mixture was stirred for6 h at −78° C. (a significant amount of starting material remained atthis point) then was allowed to warm slowly to RT and stirred overnightat RT. Excess saturated aqueous NH₄Cl was added and the mixture wasextracted with EtOAc (3×). The combined organic extracts were washedwith brine, dried (Na₂SO₄), concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAc)to give the cis-isomer Part E compound (199 mg; 50%) as a colorless oilas well as the trans-isomer Part F compound (86 mg; 22%) as a colorlessoil.

A solution of Part F compound (200 mg; 0.51 mmol) and tosylmethylisocyanide (100 mg; 0.54 mmol) in anhydrous DMSO (1 mL) was added in oneportion to a 0° C. suspension of NaH (30 mg of a 60% suspension in oil;0.75 mmol) in anhydrous Et₂O (1 mL). The mixture was allowed to warm toRT and stirred at RT for 30 min, then was partitioned between EtOAc (10mL) and H₂O (20 mL). The organic phase was washed with H₂O (2×20 mL),dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 3:1 hex:EtOAc) to give Part G compound (48 mg;22%) as an oil.

A mixture of Part G compound (48 mg; 0.11 mmol), phenyl boronic acid (20mg; 0.17 mmol), Cu(OAc)₂ (9 mg; 0.05 mmol), anhydrous pyridine (0.5 mL),2,6-lutidine (0.5 mL) and 4A molecular sieves (200 mg) in anhydroustoluene (1 mL) was heated at 70° C. (under a constant flow of air) for 5h, then was cooled to RT and filtered. This solution was partitionedbetween EtOAc and aqueous 1 N HCl (10 mL each). The organic phase waswashed with H₂O (2×10 mL), dried (Na₂SO₄) and concentrated in vacuo togive crude Part H compound as an oil, which was used in the nextreaction without further purification.

A solution of crude Part H compound in THF/1 M aqueous LiOH (2 mL of a1:1 solution) was stirred for 18 h at 100° C., then was cooled to RT andpartitioned between aqueous 1 N HCl and EtOAc (10 mL each). The organicphase was concentrated in vacuo and the residue was purified bypreparative HPLC (as for Example 66 except that the continuous gradientused was 50:50 A:B to 100% B) to give the title compound (21 mg; 38%) asa white solid.

[M+H]⁺=493.2 ¹H NMR (CDCl₃): δ 2.39 (3H, s), 2.89-2.93(2H, m), 3.00-3.09(4H, m), 4.23 (2H, t, J=7.9 Hz), 6.72 (1H, m), 6.77-6.83 (3H, m), 7.17(1H, t, J=7.9 Hz), 7.27-7.47 (8H, m), 7.76 (1H, d, J=2.6 Hz), 7.96-8.02(2H, m) ¹³C NMR (CDCl₃) δ 116.6, 159.9, 158.5, 146.2, 144.0, 139.6,131.5, 130.9, 129.7, 129.2, 128,9, 127.8, 126.7, 126.5, 126.4, 125.8,121.2 120.7, 119.1, 114.8, 114.7, 111.9, 66.1, 36.8, 28.1, 25.5, 10.2

EXAMPLE 68

A mixture of 3-hydroxyphenylacetylene (5.0 g; 42 mmol), benzyl bromide(8.7 g; 51 mmol) and K₂CO₃ (15 g; 110 mmol) in MeCN (20 mL) was heatedat 80° C. for 3 h, at which point analytical HPLC indicated thatreaction was complete. The reaction was cooled to RT and filtered. Thefiltrate was concentrated in vacuo cautiously and the residue waschromatographed (SiO₂; 5:1 hex:EtOAc) to give Part A compound (6.82 g;78%) as a clear oil.

To a −78° C. solution of Part A compound (6.82 g; 32.7 mmol) inanhydrous THF (100 mL) was added methyllithium (40 mL of a 1.4 Msolution in Et₂O; 56 mmol) dropwise. The reaction was stirred at −78° C.for 2 h, after which anhydrous dimethyl carbonate (4.7 mL; 56 mmol) wasadded in one portion. The reaction was allowed to warm to RT and stirredat RT for 30 min, after which saturated aqueous NH₄Cl (25 mL) was added.The mixture was partitioned between EtOAc and H₂O (200 mL each). Theorganic phase was washed with H₂O (2×100 mL), dried (Na₂SO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; 3:1hexane:EtOAc) to give Part B compound (5.50 g; 63%) as yellow crystals.

A solution of benzylamine (8.9 mL; 82 mmol) andchloromethyltrimethylsilane (5.0 g; 41 mmol) in MeCN (100 mL) was heatedto reflux for 16 h. The reaction was cooled to RT, filtered, and thefiltrate was concentrated in vacuo to a volume of ˜30 mL. H₂O (100 mL)was added and the mixture was extracted with hexane (2×20 mL). Thecombined organic extracts were washed with H₂O (3×20 mL), dried (MgSO₄)and concentrated in vacuo to give Part C compound (7.70 g; 49%) as anoil.

To a 0° C. solution of formaldehyde (4.6 g of a 37% aqueous solution;55.7 mmol) and 1N aqueous NaOH (5 drops) was added dropwise Part Ccompound (7.70 g; 39.8 mmol). After the mixture had been stirred at 0°C. for 10 min, MeOH (4 mL) was added, followed by K₂CO₃ (4.0 g). Themixture was allowed to warm to RT and stirred at RT for 1 h. The organicphase was separated, more K₂CO₃ (2.0 g) was added, and the reaction wasstirred at RT for 12 h. Et₂O (20 mL) was then added to the mixture,which was filtered and the filtrate was concentrated in vacuo. Theresidual oil was distilled at reduced pressure (0.5 mm Hg; 80° C.) togive Part D compound (4.67 g; 49%) as an oil.

A mixture of Part B compound (5.50 g; 21 mmol), Part D compound (4.90 g;21 mmol) and TFA (1 drop) in CH₂Cl₂ (20 mL) was stirred at RT for 3 h,then was concentrated in vacuo. The residue was chromatographed (SiO₂;hex:EtOAc 1:1) to give Part E compound (5.20 g; 63%) as a yellow oil.

To a −78° C. solution of Part E compound (t.20 g; 13 mmol) in anhydrousCH₂Cl₂ (10 mL) was added CH₃CHClOCOCl (1.80 mL; 16 mmol). The reactionmixture was stirred at −70° C. for 10 min, then was allowed to warm to−15° C. and stirred at −15° C. for 3 h. At this point, HPLC indicatedthat all starting material had been consumed. Volatiles were removed invacuo and MeOH (20 mL) was added; the solution was then stirred at RTfor 18 h, then concentrated in vacuo. A solution of the residue anddi-tert butyl dicarbonate (5 g; 23 mmol) in saturated aqueous NaHCO₃ andTHF (10 mL each) was stirred at RT for 2 h, then was partitioned betweenEtOAc and H₂O (50 mL each). The organic phase was washed with H₂O (50mL), dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 2:1 hex:EtOAc) to give Part F compound (4.77 g;90%) as an oil.

To a −70° C. solution of Part F compound (4.40 g; 10.9 mmol) inanhydrous THF (100 mL) was added dropwise DIBALH (16 mL of a 1 Msolution in hexane; 16 mmol). The reaction was stirred at −70° C. for 20min, then was warmed to RT and stirred at RT for 2 h, re-cooled to −70°C. and finally quenched by dropwise addition of MeOH (10 mL). Themixture was allowed to warm to RT, then aqueous Rochelle salt (100 mL ofa 1 M solution) was added and stirring was continued for 1 h. Themixture was partitioned between H₂O and Et₂O (200 mL each). The aqueousphase was extracted with additional Et₂O (200 mL); the combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; EtOAc:hex:Et₃N 3:1:0.08) to give Part G compound(2.57 g; 67%) as an oil.

To a 0° C. mixture of Part G compound (2.57 g; 6.73 mmol) andtriphenylphosphine (2.80 g; 10.7 mol) in CH₂Cl₂ (20 mL) was added asolution of carbon tetrabromide (3.0 g; 9.7 mmol) in CH₂Cl₂ (10 mL)dropwise over 15 min. The reaction was allowed to warm to RT and stirredat RT for 4 h, then was filtered and concentrated in vacuo. The residuewas chromatographed (SiO₂; hex:EtOAc 3:1) to give Part H compound (2.35g; 48%) as an oil.

A mixture of Part H compound (600 mg; 1.37 mmol), (Ph₃P)₄Pd^(o) (50 mg;0.045 mmol) and KHCO₃ (1.75 mg; 1.75 mmol) in anhydrous MeOH (5 mL) inan autoclave was pressurized to 100 psi with carbon monoxide (flushed 3×with CO). The reaction mixture was stirred at RT for 3 days, after whichthe CO gas was released and the mixture was filtered. The filtrate wasconcentrated in vacuo and the residue was chromatographed (SiO₂; 3:1hex:EtOAc) to give Part I compound (588 mg; 89%) as an oil.

A solution of Part I compound (66 mg, 0.155 mmol) and TFA (1 mL) inCH₂Cl₂ (1 mL) was stirred at RT for 1 h, then was concentrated in vacuoto give crude Part J compound, which was used in the next step withoutfurther purification.

A mixture of crude Part J compound, phenyl boronic acid (200 mg; 1.64mmol), Cu(OAc)₂ (10 mg; 0.06 mmol), anhydrous pyridine (0.5 mL), Et₃N(0.5 mL) and 4A molecular sieves (1 g) in anhydrous toluene (3 mL) washeated at 80° C. (under a constant flow of air) for 24 h, then wascooled to RT and filtered through a silica gel cartridge using 1:1Hex:EtOAc as eluent. The filtrates were concentrated in vacuo to givePart K compound (15 mg; 24%) as an oil.

A mixture of Part K compound (15 mg; 0.038 mmol) and 10% Pd/C (10 mg) inMeOH (5 mL) was stirred under a hydrogen atmosphere (balloon) for 1 h,then was filtered. The filtrate was concentrated in vacuo to give crudePart L compound, which was used in the next step without furtherpurification.

A mixture of crude Part L compound, 5-methyl 2-phenyl oxazole 4-ethanolmesylate (100 mg; 0.36 mmol; prepared as described in Example 11) andK₂CO₃ (500 mg; 3.0 mmol) in MeCN (6 mL) was stirred at 80° C. for 18 h,then was cooled to RT and partitioned between EtOAc and H₂O (15 mLeach). The organic phase was washed with H₂O (2×20 mL), dried (Na₂SO₄)and concentrated in vacuo. The residue was chromatographed (SiO₂; 3:1Hex:EtOAc) to give Part M compound.

A solution of Part H compound in THF/1 M aqueous LiOH (2 mL of a 1:1solution) was stirred for 2 h at 45° C., then was cooled to RT andpartitioned between aqueous 1 N HCl (5 mL) and EtOAc (10 mL). Theorganic phase was washed with H₂O (5 mL) and was concentrated in vacuo.The residue was purified by preparative HPLC (same conditions as forExample 67) to give the title compound (10 mg; 55% overall) as a whitesolid.

[M+H]⁺=479.3 ¹H NMR (CDCl₃): δ 2.38 (3H, s), 3.04 (2H, t, J=7.9 Hz),3.67 (2H, s), 4.32 (2H, t, J=7.9 Hz), 6.82 (1H, m), 7.01 (1H, d, J=8Hz), 7.05-7.17 (2H, dd, J=4, 12 Hz), 7.20-7.30 (3H, m), 7.39-7.48 (7H,m), 7.96-8.02 (2H, m)

EXAMPLE 69

To a −20° C. solution of aniline (911 μL; 0.01 mmol) in aqueous HCl (3.5mL of a 12 N solution +15 mL H₂O) was added dropwise a solution of NaNO₂(828 mg; 0.012 mmol) in H₂O (5 mL). The diazonium ion solution wasstirred at −20° C. for 15 min, then was added dropwise to a −2° C.mixture of ethyl 4-methoxybenzoyl acetate (2.22 g; 0.01 mmol) and sodiumacetate (6.0 g; 73 mmol) in EtOH (12 mL). The reaction was stirred at−2° C. for 20 min, after which mixture was partitioned between EtOAc andH₂O (30 mL each). The organic phase was washed with H₂O (2×30 mL) anddried (Na₂SO₄). The residue was chromatographed (SiO₂; 5:1 Hex:EtOAc) toafford Part A compound (1.17 g; 35%) as a yellow oil (which stillcontained a small amount of ethyl 4-methoxybenzoyl acetate).

A mixture of Part A compound (1.17 g; 3.59 mmol), Cu(II)Cl₂.2H₂O (1.83g; 10.7 mmol) and NH₄OAc (2.76 g; 35.9 mmol) in EtOH (20 mL) was heatedin a sealed tube at 100° C. for 18 h. The reaction was cooled to RT andpartitioned between EtOAc (50 mL) and H₂O (20 mL). The organic phase waswashed with H₂O (2×20 mL), dried (Na₂SO₄) and concentrated in vacuo. Theresidue was recrystallized from hex:EtOAc:EtOH (1:1:1) to give Part Bcompound (528 mg; 45%) as yellow crystals.

To a −70° C. solution of Part B compound (250 mg; 0.773 mmol) in CH₂Cl₂(1 mL) was added dropwise BBr₃ (2.0 mL of a 1M solution in CH₂Cl₂). Themixture was allowed to warm to RT and stirred at RT for 4 h, after whichMeOH (2 mL) was cautiously added and stirring was continued at RTovernight. Volatiles were removed in vacuo, and the residue waschromatographed (SiO₂; 3:1 hex:EtOAc) to give Part C compound (210 mg;92%) as an oil.

A mixture of Part C compound, 5-methyl 2-phenyl oxazole 4-ethanolmesylate (281 mg; 1.0 mmol; prepared as described in Example 11) andK₂CO₃ (829 mg; 6.0 mmol) in MeCN (10 mL) was stirred at 80° C. for 18 h,then was cooled to RT and partitioned between EtOAc (10 mL) and H₂O (20mL). The organic phase was washed with H₂O (2×20 mL), dried (Na₂SO₄) andconcentrated in vacuo to give crude Part D compound, which was used inthe next step without further purification.

A solution of crude Part D compound in THF/1 M aqueous LiOH (10 mL of a1:1 solution) was stirred for 3 h at 50° C., then was cooled to RT andpartitioned between aqueous 1 N HCl and EtOAc (10 mL each). The organicphase was washed with H₂O (2×10 mL), dried (Na₂SO₄) and concentrated invacuo to give the title compound (300 mg; 83%) as yellow crystals.

[M+H]⁺: 467.13 ¹H NMR (CDCl₃): δ 2.32 (3H, s), 2.98 (2H, t, J=6.6 Hz),4.25 (2H, t, J=6.6 Hz), 6.86-6.91 (2H, d, J=8.8 Hz), 7.30-7.38 (4H, m),7.40-7.48 (2H, t, J=8.4 Hz), 7.87-7.7.93 (4H, m), 8.0-8.12 (2H, d, J=7.5Hz).

EXAMPLE 70

A solution of Example 69 (120 mg; 0.26 mmol) and oxalyl chloride (6 mLof a 2 N solution in CH₂Cl₂; 12.0 mmol) was heated at 50° C. in a sealedtube for 5 h, then was cooled to RT and concentrated in vacuo. A 0° C.solution of diazomethane [generated as in Example 65 from1-methyl-3-nitro-1-nitrosoguanidine (441 mg; 3.0 mmol), Et₂O (10 mL) and40% aqueous KOH (5 mL)] was cautiously added to the crude acid chlorideand the reaction was stirred at 0° C. for 1 h. Volatiles were removed invacuo and the residue was chromatographed (SiO2; 3:1 hex:EtOAc) to givePart A compound (82 mg; 64%) as a yellow solid.

A mixture of Part A compound (82 mg; 0.167 mmol), silver benzoate (46mg; 0.20 mmol) and anhydrous Et₃N (1 mL; 7.2 mmol) in anhydrous MeOH (5mL) was stirred at RT for 1 h (dark solution), after which volatileswere removed in vacuo to give crude Part B compound, which was used inthe next step without further purification.

A solution of crude Part B compound in THF/1 M aqueous LiOH (10 mL of a1:1 solution) was stirred for 1 h at 50° C., then was cooled to RT andpartitioned between aqueous 1 N HCl and EtOAc (10 mL each). The organicphase was washed with H₂O (2×10 mL), dried (Na₂SO₄) and concentrated invacuo. The residue was purified by preparative HPLC (same conditions asfor Example 67) to give the title compound (13.8 mg; 17%) as a whitesolid.

[M+H]⁺: 481.1 ¹H NMR (CDCl₃): δ 2.45 (3H, s), 3.11 (2H, t, J=5.72 Hz),3.98 (2H, s), 4.27 (2H, t, J=5.7 Hz), 6.95-6.96 (2H, d, J=8.8 Hz), 7.33(1H, t, J=7.0 Hz), 7.44-7.55 (5H, m), 7.63 (2H, d, J=8.8 Hz), 8.01 (2H,d, J=7.7 Hz), 8.07 (2H, d, J=7.9 Hz)

EXAMPLE 71

A mixture of Example 3 Part E compound (483 mg; 1.26 mmol) and KOH (1.0g; 17.8 mmol) in EtOH (10 mL) was heated at 160° C. in a sealed tube for2 h, then was cooled to RT and partitioned between EtOAc (20 mL) andaqueous 1N HCl (30 mL). The organic phase was washed with H₂O (2×30 mL),dried (Na₂SO₄) and concentrated in vacuo to give Part A compound as anoil, which was used in the next step without further purification.

A solution of crude Part A compound and oxalyl chloride (1 mL; 11.5mmol) in CH₂Cl₂ (10 mL) was stirred at RT for 2 h, after which volatileswere removed in vacuo to give Part B compound (410 mg; 99%) as a brownsolid, which was used in the next step without further purification.

To a solution of crude Part B compound (41 mg; 0.125 mmol) in CH₂Cl₂ (5mL) was added a solution of ethereal diazomethane [generated from1-methyl-3-nitro-1-nitrosoguanidine (440 mg; 3 mmol) and 40% aqueous KOH(1.3 mL) as described for Example 65 Part A compound] was allowed tostand for 1 h at 0° C. Excess diazomethane in the reaction was quenchedwith acetic acid; volatiles were then removed in vacuo. The residue waschromatographed (SiO₂; hex:EtOAc 3:1) to give Part C compound (21 mg;51%) as a yellow oil.

To a solution of Part C compound (21 mg; 0.063 mmol) in anhydrous MeOH(4 mL) was added silver benzoate (18 mg; 0.08 mmol) followed by Et₃N (28μL; 0.2 mmol) dropwise. The reaction mixture was stirred at RT for 2 h,then was concentrated in vacuo. The residue was chromatographed (SiO₂;hexane:EtOAc 1:1) to give Part D compound (21 mg; 90%) as an oil.

To a −70° C. solution of Part D compound (23 mg; 0.068 mmol) in CH₂Cl₂(1 mL) was added dropwise BBr₃ (0.8 mL of a 1 M solution in CH₂Cl₂; 0.80mmol). The mixture was allowed to warm to RT and stirred at RT for 2 h,after which MeOH (1 mL) was cautiously added and stirring was continuedat RT for 3 h. Volatiles were removed in vacuo, and the residue waschromatographed (SiO₂; 3:1 hex:EtOAc) to give Part F compound (21 mg;95%) as a oil.

A mixture of Part F compound (21 mg; 0.065 mmol), 5-methyl 2-phenyloxazole 4-ethanol mesylate (28 mg; 0.10 mmol; prepared as described inExample 11) and K₂CO₃ (690 mg; 5.0 mmol) in DMF (2 mL) was stirred at80° C. for 18 h, then was cooled to RT and partitioned between EtOAc (10mL) and H₂O (10 mL). The organic phase was washed with H₂O (2×10 mL),dried (Na₂SO₄) and concentrated in vacuo to give crude Part G compoundas an oil, which was used in the next step without further purification.

A solution of crude Part H compound in THF/1 M aqueous LiOH (2 mL of a1:1 solution) was stirred for 3 h at 50° C., then was cooled to RT andpartitioned between aqueous 1 N HCl (5 mL) and EtOAc (10 mL). Theorganic phase was washed with H₂O (10 mL), dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC(same conditions as Example 66) to afford the title compound (8 mg; 25%over 2 steps) as a white solid.

[M+H]⁺: 495.3 ¹H NMR (DMSO-d6): δ 2.35 (3H, s), 2.92 (2H, t, J=6.6 Hz),3.68 (2H, s), 4.01 (2H, s), 4.18 (2H, t, J=6.6 Hz), 6.87 (2H, d, J=6.6Hz), 7.17 (2H, d, J=6.6 Hz), 7.38 (1H, t, J=7.5 Hz), 7.48-7.55 (5H, m),7.90-7.94 (4H, m), 12.64 (1H, s)

1. A compound which has the structure

wherein m is 0, 1 or 2; n=0, 1 or 2; Q is C or N A is (CH₂)_(x) where xis 1 to 5; or A is (CH₂)_(x) ¹, where x¹ is 2 to 5, with an alkenyl bondor an alkynyl bond embedded in the chain; or A is —(CH₂)_(x)²—O—(CH₂)_(x) ³— where x² is 0 to 5 and x³ is 0 to 5, provided that atleast one of x² and x³ is other than 0, X₁ is CH or N X₂ is C, N, O orS; X₃ is C, N, O or S; X₄ is C, N, O or S, provided that at least one ofX₂, X₃ and X₄ is N; X₅ is C, N, O or S; X₆ is C or N; X₇ is C, N, O orS, provided that at least one of X₅, X₆ or X₇ is N; and where in each ofX₁ through X₇, as defined above, C may include CH; R¹ is H or alkyl; R²is H, alkyl, alkoxy, halogen, amino or substituted amino; R^(2a), R^(2b)and R^(2c) are the same or different and are selected from H, alkyl,alkoxy, halogen, amino or substituted amino; R³ and R^(3a) are the sameor different and are independently selected from H, alkyl, arylalkyl,aryloxycarbonyl, alkyloxycarbonyl, alkynyloxycarbonyl,alkenyloxycarbonyl, arylcarbonyl, alkylcarbonyl, aryl, heteroaryl,alkyl(halo)aryloxycarbonyl, alkyloxy(halo)aryloxycarbonylcycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl,cycloheteroalkyl, heteroarylcarbonyl, heteroaryl-heteroarylalkyl,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino,alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino,heteroaryl-heteroarylcarbonyl, alkylsulfonyl, alkenylsulfonyl,heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl, heteroarylalkyl,aminocarbonyl, substituted aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, heteroarylalkenyl, cycloheteroalkylheteroarylalkyl,hydroxyalkyl, alkoxy, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl,alkylaryloxycarbonyl, arylheteroarylalkyl, arylalkylarylalkyl,aryloxyarylalkyl, alkynyloxycarbonyl, haloalkoxyaryloxycarbonyl,alkoxycarbonylaryloxycarbonyl, aryloxyaryloxycarbonyl,arylsulfinylarylcarbonyl, arylthioarylcarbonyl,alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl,heteroaryloxyarylalkyl, aryloxyarylcarbonyl,aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl,aryloxyalkyloxycarbonyl arylalkylsulfonyl, arylthiocarbonyl,arylalkenylsulfonyl, hateroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl,heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl,aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl,arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl,alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl,heteroarylarylalkyl, arylcarbonylheteroarylalkyl,heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkylor aminocarbonylarylarylalkyl; Y is CO₂R⁴ (where R⁴ is H or alkyl, or aprodrug ester) or Y is a C-linked 1-tetrazole, a phosphinic acid of thestructure P(O)(OR^(4a))R⁵, (where R^(4a) is H or a prodrug ester, R⁵ isalkyl or aryl) or a phosphonic acid of the structure P(O) (OR^(4a))₂;(CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³, (CH₂)_(m), and(CH₂)_(n) may be optionally substituted with 1, 2 or 3 substituents;including all stereoisomers thereof, a prodrug ester thereof, and apharmaceutically acceptable salt thereof.
 2. A compound having thestructure

wherein m is 0, 1 or 2; n=0, 1 or 2; Q is C or N x² is 0 to 5 and x³ is0 to 5, provided that at least one of x² and x³ is other than 0, X₂ isC, N, O or S; X₃ is C, N, O or S; X₄ is C, N, O or S, provided that atleast one of X₂, X₃ and X₄ is N; and where in each of X₂ through X₄, asdefined above, C may include CH; R¹ is H or alkyl; R² is H, alkyl,alkoxy, halogen, amino or substituted amino; R^(2a), R^(2b) and R^(2c)are the same or different and are selected from H, alkyl, alkoxy,halogen, amino or substituted amino; R³ and R^(3a) are the same ordifferent and are independently selected from H, alkyl, arylalkyl,aryloxycarbonyl, alkyloxycarbonyl, alkynyloxycarbonyl,alkenyloxycarbonyl, arylcarbonyl, alkylcarbonyl, aryl, heteroaryl,alkyl(halo)aryloxycarbonyl, alkyloxy(halo)aryloxycarbonylcycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl,cycloheteroalkyl, heteroarylcarbonyl, heteroaryl-heteroarylalkyl,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino,alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino,heteroaryl-heteroarylcarbonyl, alkylsulfonyl, alkenylsulfonyl,heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl, heteroarylalkyl,aminocarbonyl, substituted aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, heteroarylalkenyl, cycloheteroalkylheteroarylalkyl,hydroxyalkyl, alkoxy, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl,alkylaryloxycarbonyl, arylheteroarylalkyl, arylalkylarylalkyl,aryloxyarylalkyl, alkynyloxycarbonyl, haloalkoxyaryloxycarbonyl,alkoxycarbonylaryloxycarbonyl, aryloxyaryloxycarbonyl,arylsulfinylarylcarbonyl, arylthioarylcarbonyl,alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl,heteroaryloxyarylalkyl, aryloxyarylcarbonyl,aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl,aryloxyalkyloxycarbonyl arylalkylsulfonyl, arylthiocarbonyl,arylalkenylsulfonyl, hateroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl,heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl,aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl,arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl,alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl,heteroarylarylalkyl, arylcarbonylheteroarylalkyl,heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkylor aminocarbonylarylarylalkyl; (CH₂)_(x) ², (CH₂)_(x) ³, (CH₂)_(m), and(CH₂)_(n) may be optionally substituted with 1, 2 or 3 substituents;including all stereoisomers thereof, a prodrug ester thereof, and apharmaceutically acceptable salt thereof.
 3. The compound as defined inclaim 1 having the structure


4. The compound as defined in claim 1 having structure


5. The compound as defined in claim 1 wherein (CH₂)_(x), (CH₂)_(x) ¹,(CH₂)_(x) ², (CH₂)_(x) ³ are alkylene, alkenylene, allenyl, oralkynylene.
 6. The compound as defined in claim 1 wherein X₁ is CH. 7.The compound as defined in claim 1 wherein X is N.
 8. The compound asdefined in claim 1 having the structure

wherein R¹ is alkyl, x² is 1, 2 or 3, m is 0 or 1, or (CH₂)_(m) is CHOHor CH-alkyl, n is 1, (CH₂)_(n) is a bond or CH₂, X₂, X₃, and X₄represent a total of 1, 2 or 3 nitrogens, R³ is aryl, arylalkyl orheteroaryl and R^(3a) is H or alkyl.
 9. The compound as defined in claim8 wherein R¹ is CH₃, and R³ is phenyl or phenyl substituted with alkyl,polyhaloalkyl, halo or alkoxy.
 10. The compound as defined in claim 1having the structure


11. A pharmaceutical composition comprising a compound as defined inclaim 1 and a pharmaceutically acceptable carrier therefor.
 12. A methodfor lowering blood glucose levels, or for treating diabetes whichcomprises administering to a patient in need of treatment atherapeutically effective amount of a compound as defined in claim 1.13. A method for treating a premalignant disease, an early malignantdisease, a malignant disease, or a dysplastic disease, which comprisesadministering to a patient in need of treatment a therapeuticallyeffective amount of a compound as defined in claim
 1. 14. Apharmaceutical combination comprising a compound as defined in claim 1and a lipid-lowering agent, a lipid modulating agent, an antidiabeticagent, an anti-obesity agent, an antihypertensive agent, a plateletaggregation inhibitor, and/or an antiosteoporosis agent, wherein theantidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, aglucosidase inhibitor, a PPARγ agonist, a PPAR α/γ dual agonist, anSGLT2 inhibitor, a DP4 inhibitor, an aP2 inhibitor, an insulinsensitizer, a glucagon-like peptide-1 (GLP-1), insulin and/or ameglitinide, wherein the anti-obesity agent is a beta 3 adrenergicagonist, a lipase inhibitor, a serotonin (and dopamine) reuptakeinhibitor, a thyroid receptor agonist, an aP2 inhibitor and/or ananorectic agent, wherein the lipid lowering agent is an MTP inhibitor,an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, afibric acid derivative, an upregulator of LDL receptor activity, alipoxygenase inhibitor, or an ACAT inhibitor, wherein theantihypertensive agent is an ACE inhibitor, angiotensin II receptorantagonist, NEP/ACE inhibitor, calcium channel blocker and/orβ-adrenergic blocker.
 15. The combination as defined in claim 12 whereinthe antidiabetic agent is 1, 2, 3 or more of metformin, glyburide,glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose,miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, G1-262570,isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677,repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297,AC2993, LY315902, P32/98 and/or NVP-DPP-728A, wherein the anti-obesityagent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine,topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine,and/or mazindol, wherein the lipid lowering agent is pravastatin,lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin,itavastatin, visastatin, fenofibrate, gemfibrozil, clofibrate,avasimibe, TS-962, MD-700, cholestagel, niacin and/or LY295427, whereinthe antihypertensive agent is an ACE inhibitor which is captopril,fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril,ramipril or moexipril; an NEP/ACE inhibitor which is omapatrilat,[S[(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat) or CGS 30440; an angiotensin II receptor antagonistwhich is irbesartan, losartan or valsartan; amlodipine besylate,prazosin HCl, verapamil, nifedipine, nadolol, propranolol, carvedilol,or clonidine HCl, wherein the platelet aggregation inhibitor is aspirin,clopidogrel, ticlopidine, dipyridamole or ifetroban.
 16. A method fortreating insulin resistance, hyperglycemia, hyperinsulinemia, orelevated blood levels of free fatty acids or glycerol, hyperlipidemia,obesity, Syndrome X, dysmetabolic syndrome, inflammation, diabeticcomplications, impaired glucose homeostasis, impaired glucose tolerance,hypertriglyceridemia or atherosclerosis which comprises administering toa mammalian species in need of treatment a therapeutically effectiveamount of a pharmaceutical combination as defined in claim
 14. 17. Themethod as defined in claim 13 wherein the disease is a liposarcoma or anepithelial tumor.
 18. The method as defined in claim 17 wherein theepithelial tumor is a tumor of the breast, prostate, colon, ovaries,stomach or lung.
 19. A method for treating irritable bowel syndrome,Crohn's disease, gastric ulceritis or osteroporosis, or psoriasis, orfor treating obesity, insulin resistance, dyslipidemia, cardiovasculardiseases and liver abnormalities, which comprises administering to amammalian species in need of treatment a therapeutically effectiveamount of a compound as defined in claim
 1. 20. A method for treatingobesity and cardiovascular disease through altering the expression of agene selected from the following: HMGic, glycerol-PO₄ dehydrogenase,fatty acid transport protein, G-protein coupled receptor 26,adipophilin, keratinocyte, fatty acid binding protein, angiotensinogen,PAI-1, and renin, through administration of a dual PPARgammaantagonist/PPARalpha agonist.